24: Seikagaku. 2005 Dec;77(12):1481-96.
Suzuki T.
Department of Chemistry and Biotechnology, Graduate School of Engineering,
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Publication Types:
Review
PMID: 16440752 [PubMed - indexed for MEDLINE]
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Publication Types:
Review
PMID: 16440752 [PubMed - indexed for MEDLINE]
23: Rinsho Shinkeigaku. 2005 Nov;45(11):808-10.
Nakano I.
Neurology, Jichi Medical School.
As dementing diseases are too numerous to refer to all of them, I confine my
description to the neuropathology of amyotrophic lateral sclerosis with dementia
(ALSD), and cerebral vascular pathology of three unique vascular diseases
causing dementia. 1) ALSD: The cortical neuropathology of this condition exhibit
two main unique profiles in addition to mainly temporal lobe-located cortical
changes. One is ubiquitin-positive intraneuronal cytoplasmic inclusions, and the
other a localized neuronal degeneration in the transitional zone between the
hippocampal CA1 and subiculum. 2) Cerebral autosomal recessive arteriopathy with
subcortical infarcts and leukoencephalopathy (CARASIL): The characteristic
vascular change of this condition is marked intimal thickening of the middle and
small arteries with relatively preserved smooth muscle cells in the media. The
scalp arteries escape this lesion, indicating non-ischemic pathomechanisms for
the baldness seen in this condition. 3) Cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL): The main lesions of
the cerebral vessels are smooth muscle cell degeneration of deep perforating and
small meningeal arteries with deposition of granular osomiophilic material in
the media of the affected vessels. 4) Sneddon syndrome: This condition
characterized by livedo reticularis and recurrent multiple infarctions shows
marked sclerotic changes in the deep perforating arterioles and main cerebral
arteries with relatively spared middle- and small-sized meningeal arteries.
Publication Types:
English Abstract
PMID: 16447731 [PubMed - indexed for MEDLINE]
Nakano I.
Neurology, Jichi Medical School.
As dementing diseases are too numerous to refer to all of them, I confine my
description to the neuropathology of amyotrophic lateral sclerosis with dementia
(ALSD), and cerebral vascular pathology of three unique vascular diseases
causing dementia. 1) ALSD: The cortical neuropathology of this condition exhibit
two main unique profiles in addition to mainly temporal lobe-located cortical
changes. One is ubiquitin-positive intraneuronal cytoplasmic inclusions, and the
other a localized neuronal degeneration in the transitional zone between the
hippocampal CA1 and subiculum. 2) Cerebral autosomal recessive arteriopathy with
subcortical infarcts and leukoencephalopathy (CARASIL): The characteristic
vascular change of this condition is marked intimal thickening of the middle and
small arteries with relatively preserved smooth muscle cells in the media. The
scalp arteries escape this lesion, indicating non-ischemic pathomechanisms for
the baldness seen in this condition. 3) Cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL): The main lesions of
the cerebral vessels are smooth muscle cell degeneration of deep perforating and
small meningeal arteries with deposition of granular osomiophilic material in
the media of the affected vessels. 4) Sneddon syndrome: This condition
characterized by livedo reticularis and recurrent multiple infarctions shows
marked sclerotic changes in the deep perforating arterioles and main cerebral
arteries with relatively spared middle- and small-sized meningeal arteries.
Publication Types:
English Abstract
PMID: 16447731 [PubMed - indexed for MEDLINE]
22: Rinsho Shinkeigaku. 2005 Nov;45(11):973-5.
Yokota T.
Department of Neurology and Neurological Science, Tokyo Medical and Dental
University.
In many of autosomal dominant diseases such as familial amyotrophic lateral
sclerosis (ALS) with Cu/Zn superoxide dismutase (SOD1) mutation, a missense
point mutation may induce the disease by its gain of adverse property. Similar
'gain of toxic function' of mutant protein is predicted to cause cell death in
other autosomal dominant neurodegenerative diseases such as familial Alzheimer
disease, prion disease, polyglutamine diseases and Parkinson disease. In all
these familial diseases, one rational approach to therapy is to develop a method
to specifically eliminate the aberrant protein. Duplex of 21-nt RNA, known as
siRNA, has recently emerged as a powerful tool to silence gene. Mutant-allele
specific gene silencing with siRNA was showed in familial ALS and Machado-Joseph
diseases. We made the transgenic (Tg) mouse of modified small interfering RNA
(siRNA). By crossing this anti-SOD1 siRNA Tg mouse with a SOD1(G93A) Tg mouse as
a model for ALS, siRNA halted the development of disease by inhibiting mutant
G93A SOD1. Our results support the feasibility of utilizing siRNA-based gene
therapy of neurodegenerative diseases of autosomal dominant inheritance.
Publication Types:
English Abstract
PMID: 16447777 [PubMed - indexed for MEDLINE]
Yokota T.
Department of Neurology and Neurological Science, Tokyo Medical and Dental
University.
In many of autosomal dominant diseases such as familial amyotrophic lateral
sclerosis (ALS) with Cu/Zn superoxide dismutase (SOD1) mutation, a missense
point mutation may induce the disease by its gain of adverse property. Similar
'gain of toxic function' of mutant protein is predicted to cause cell death in
other autosomal dominant neurodegenerative diseases such as familial Alzheimer
disease, prion disease, polyglutamine diseases and Parkinson disease. In all
these familial diseases, one rational approach to therapy is to develop a method
to specifically eliminate the aberrant protein. Duplex of 21-nt RNA, known as
siRNA, has recently emerged as a powerful tool to silence gene. Mutant-allele
specific gene silencing with siRNA was showed in familial ALS and Machado-Joseph
diseases. We made the transgenic (Tg) mouse of modified small interfering RNA
(siRNA). By crossing this anti-SOD1 siRNA Tg mouse with a SOD1(G93A) Tg mouse as
a model for ALS, siRNA halted the development of disease by inhibiting mutant
G93A SOD1. Our results support the feasibility of utilizing siRNA-based gene
therapy of neurodegenerative diseases of autosomal dominant inheritance.
Publication Types:
English Abstract
PMID: 16447777 [PubMed - indexed for MEDLINE]
21: Rinsho Shinkeigaku. 2005 Nov;45(11):982-4.
Shin K.
Department of Neurology, Graduate School of Medicine, The University of Tokyo.
AMPA receptor-mediated neuronal death is initiated by exaggerated Ca2+ influx
through AMPA receptor channels, and the Ca2+ permeability of the AMPA receptor
ion channel depends strongly upon the presence or absence in its composition of
an edited GluR2 subunit whose glutamine (Q) residue is substituted by arginine
(R) at the Q/R site due to RNA editing. The pivotal role of the RNA editing at
the GluR2 Q/R site in neuronal death has been clearly demonstrated in animal
experiments and its deficiency is a direct cause of neuronal death. We
demonstrated that the editing efficiency at the GluR2 mRNA Q/R site varied
greatly, from 0% to 100%, among the single motoneurons of each individual with
ALS, whereas it remained 100% among those of normal controls. In addition, the
editing efficiency was more than 99% in the cerebellar Purkinje cells of ALS,
spinocerebellar degeneration and normal control groups. By contrast, there was
no significant difference as to both the amount and the proportion to total
GluRs mRNA of GluR2 mRNA between normal and ALS motoneurons. Thus, marked GluR2
underediting in ALS motoneurons occurs in a disease specific and region
selective manner, and may be closely relevant to ALS etiology.
Publication Types:
English Abstract
PMID: 16447780 [PubMed - indexed for MEDLINE]
Shin K.
Department of Neurology, Graduate School of Medicine, The University of Tokyo.
AMPA receptor-mediated neuronal death is initiated by exaggerated Ca2+ influx
through AMPA receptor channels, and the Ca2+ permeability of the AMPA receptor
ion channel depends strongly upon the presence or absence in its composition of
an edited GluR2 subunit whose glutamine (Q) residue is substituted by arginine
(R) at the Q/R site due to RNA editing. The pivotal role of the RNA editing at
the GluR2 Q/R site in neuronal death has been clearly demonstrated in animal
experiments and its deficiency is a direct cause of neuronal death. We
demonstrated that the editing efficiency at the GluR2 mRNA Q/R site varied
greatly, from 0% to 100%, among the single motoneurons of each individual with
ALS, whereas it remained 100% among those of normal controls. In addition, the
editing efficiency was more than 99% in the cerebellar Purkinje cells of ALS,
spinocerebellar degeneration and normal control groups. By contrast, there was
no significant difference as to both the amount and the proportion to total
GluRs mRNA of GluR2 mRNA between normal and ALS motoneurons. Thus, marked GluR2
underediting in ALS motoneurons occurs in a disease specific and region
selective manner, and may be closely relevant to ALS etiology.
Publication Types:
English Abstract
PMID: 16447780 [PubMed - indexed for MEDLINE]
20: Rinsho Shinkeigaku. 2005 Nov;45(11):991-3.
Kondo K.
Department of Neurology, Yoka Hospital.
The author reports network to support patients with amyotrophic lateral
sclerosis in the Hyogo prefecture. Three types of network are working, which are
the network in the multidisciplinary team in the hospital, the medico-welfare
network in the area and the network intra-hospitals in the prefecture. We have
to establish effective network with a passion, a mission and an action.
Publication Types:
English Abstract
PMID: 16447783 [PubMed - indexed for MEDLINE]
Kondo K.
Department of Neurology, Yoka Hospital.
The author reports network to support patients with amyotrophic lateral
sclerosis in the Hyogo prefecture. Three types of network are working, which are
the network in the multidisciplinary team in the hospital, the medico-welfare
network in the area and the network intra-hospitals in the prefecture. We have
to establish effective network with a passion, a mission and an action.
Publication Types:
English Abstract
PMID: 16447783 [PubMed - indexed for MEDLINE]
19: Ideggyogy Sz. 2005 Nov 20;58(11-12):417-24.
Aranyi Z.
Semmelweis Egyetem, Altalanos Orvostudomanyi Kar, Neurologiai Klinika, Budapest.
zsuzsi@neur.sote.hu
Transcranial magnetic stimulation (TMS) is a relatively new technique that
allows painless activation of cortical motor neurons. In the clinical setting,
TMS is primarily used for the investigation of the corticospinal tract in
various neurological diseases, being especially useful in the detection of
subclinical dysfunction. In addition to the motor cortex, TMS can be applied to
examine other structures inaccessible to electrical stimulation, such as the
canalicular portion of the facial nerve. In healthy individuals, TMS can be
utilized to monitor excitability changes of the motor system in various
situations and muscles, providing valuable information to the understanding of
the physiology of motor control. Furthermore, TMS can be used to explore
interhemispheric connections as well as intracortical inhibitory and excitatory
processes both in health and disease. Finally, with the help of TMS cortical
maps of the representation areas of muscles can be constructed, giving insight
to both short and long-term cortical plasticity and to the reorganisation of the
motor cortex following damage to the brain or acquisition of new motor skills.
Publication Types:
English Abstract
Review
PMID: 16491566 [PubMed - indexed for MEDLINE]
Aranyi Z.
Semmelweis Egyetem, Altalanos Orvostudomanyi Kar, Neurologiai Klinika, Budapest.
zsuzsi@neur.sote.hu
Transcranial magnetic stimulation (TMS) is a relatively new technique that
allows painless activation of cortical motor neurons. In the clinical setting,
TMS is primarily used for the investigation of the corticospinal tract in
various neurological diseases, being especially useful in the detection of
subclinical dysfunction. In addition to the motor cortex, TMS can be applied to
examine other structures inaccessible to electrical stimulation, such as the
canalicular portion of the facial nerve. In healthy individuals, TMS can be
utilized to monitor excitability changes of the motor system in various
situations and muscles, providing valuable information to the understanding of
the physiology of motor control. Furthermore, TMS can be used to explore
interhemispheric connections as well as intracortical inhibitory and excitatory
processes both in health and disease. Finally, with the help of TMS cortical
maps of the representation areas of muscles can be constructed, giving insight
to both short and long-term cortical plasticity and to the reorganisation of the
motor cortex following damage to the brain or acquisition of new motor skills.
Publication Types:
English Abstract
Review
PMID: 16491566 [PubMed - indexed for MEDLINE]
18: J Herb Pharmacother. 2005;5(3):23-31.
The use of herbal supplements and alternative therapies by patients with
amyotrophic lateral sclerosis (ALS).
Vardeny O, Bromberg MB.
University of Winconsin-Madison School of Pharmacy, Madison, WI, USA.
OBJECTIVES: Alternative medicine is widely used in all industrialized Western
countries. However, there are no published data regarding the use of botanical
or herbal supplements in Ayotrophic Lateral Sclerosis (ALS). Our goal was to
survey patients with ALS in our clinic regarding their use of herbal
supplements, vitamins, and other therapies or compounds. METHODS: Study subjects
participated in the University of Utah Motor Neuron Disease Clinic. An anonymous
questionnaire was mailed and designed to assess the following: disease duration
and onset site, use of riluzole, alternative therapies (i.e., homeopathy,
acupuncture), vitamins, herbal supplements, and other compounds, sources of
information about herbal supplements or vitamins, estimated monthly expenditure
on vitamins, herbal supplements, and other compounds, and expectations from
herbal supplements/vitamins. RESULTS: Fifty-three subjects participated; mean
age 60 years old (range 39-83 years), 15 females, 38 males. Symptom duration
averaged 1-5 years (45 limb onset, 8 bulbar onset). Thirty-two percent took
riluzole and 42% used herbal supplements, 70% took vitamins, and 21% used other
compounds (prescription medications used for ALS, but not indicated for ALS).
Fifteen percent used alternative therapies. Information about herbal medicines
was obtained mostly via friends and relatives (n = 17), a physician (n = 20),
and the Internet (n = 9). Our patients selected improvement of general well
being and slowing of disease progression most often as reasons for using these
therapies. CONCLUSIONS: Our study demonstrated that almost half of patients
surveyed utilized herbals supplements, and two thirds of ALS study subjects took
vitamins. Twenty-one percent used unproven prescription drugs, and 15% used
other alternative therapies.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16520295 [PubMed - indexed for MEDLINE]
17: Biofactors. 2005;25(1-4):117-26.
Clinical trials of coenzyme Q10 in neurological disorders.
Shults CW, Haas R.
Department of Neurosciences, University of California, San Diego, La Jolla, 92093, USA. cshults@ucsd.edu
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16873936 [PubMed - indexed for MEDLINE]
16: Arch Environ Occup Health. 2005 Jul-Aug;60(4):223-8.
Rapid detection of sewage sample polioviruses by integrated cell culture polymerase chain reaction.
* Chowdhary R,
* Shukla A,
* Datta T,
* Dhole TN.
Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
The authors' objective in this study was to introduce and evaluate integrated cell culture polymerase chain reaction (ICC-PCR) as a technique for the rapid screening of poliovirus in sewage samples. Researchers are in the last stage of poliomyelitis eradication; however, in a densely populated country such as India, time is the prime factor in the identification of poliovirus circulation and transmission because this virus follows the fecal-oral route for transmission and is excreted in nature. The authors used ICC-PCR to detect poliovirus in sewage samples, and they compared this nonconventional method with conventional cell culture methods to determine sensitivity, accuracy, and the time from sample collection to final results. The ICC-PCR method provided results within 4-5 days of sewage-sample collection; in contrast, the conventional method takes more than 18 days to provide such results. The ICC-PCR method proved to be sensitive, reproducible, and accurate, as well as rapid in its screening of sewage samples for poliovirus. This diagnostic tool may indeed prove quite useful in polio eradication.
PMID: 17214293 [PubMed - indexed for MEDLINE]
15: Neurol Clin Neurophysiol. 2005 Dec 20;2005:3.
MRI in amyotrophic lateral sclerosis: hyperintensity of the corticospinal tract.
* Kriaa S,
* Zbidi M,
* Hafsa C,
* Golli M,
* Gannouni A.
Department of Radiology, Fattouma Bourguiba Hospital, Monastir, Tunisia.
Amyotrophic lateral sclerosis is the most common form of motor neuron disease. The diagnosis is based on clinical and electromyography criteria. The primary role of imaging in amyotrophic lateral sclerosis is to exclude other causes such as cervical degenerative disk disease, Chiari malformation or multiple sclerosis. Imaging is also helpful in atypical cases of the disease.
PMID: 17139392 [PubMed - indexed for MEDLINE]
MRI in amyotrophic lateral sclerosis: hyperintensity of the corticospinal tract.
* Kriaa S,
* Zbidi M,
* Hafsa C,
* Golli M,
* Gannouni A.
Department of Radiology, Fattouma Bourguiba Hospital, Monastir, Tunisia.
Amyotrophic lateral sclerosis is the most common form of motor neuron disease. The diagnosis is based on clinical and electromyography criteria. The primary role of imaging in amyotrophic lateral sclerosis is to exclude other causes such as cervical degenerative disk disease, Chiari malformation or multiple sclerosis. Imaging is also helpful in atypical cases of the disease.
PMID: 17139392 [PubMed - indexed for MEDLINE]
14: Neurol Clin Neurophysiol. 2005 Feb 22;2005:1.
EMG vagus nerve stimulator artifact.
* Bejanishvili S,
* Osborne LE,
* Messenger K,
* Olejniczak P,
* Gutierrez A.
Louisiana State University Health Sciences Center, Department of Neurology, New Orleans, LA 70112, USA. sbajanishvili@yahoo.com
EMG artifact produced by a VNS stimulator is described. A patient with a VNS stimulator underwent an EMG study for suspected ALS. Artifacts that appeared similar to positive sharp waves or fibrillations were noted that could produce a false clinical diagnosis. These VNS-EMG artifacts matched well with the VNS generator's set parameters. We conclude that EMG findings must be interpreted with caution in patients with VNS implants and also that EMG may have a possible monitoring value for VNS activity.
PMID: 17139390 [PubMed - indexed for MEDLINE]
EMG vagus nerve stimulator artifact.
* Bejanishvili S,
* Osborne LE,
* Messenger K,
* Olejniczak P,
* Gutierrez A.
Louisiana State University Health Sciences Center, Department of Neurology, New Orleans, LA 70112, USA. sbajanishvili@yahoo.com
EMG artifact produced by a VNS stimulator is described. A patient with a VNS stimulator underwent an EMG study for suspected ALS. Artifacts that appeared similar to positive sharp waves or fibrillations were noted that could produce a false clinical diagnosis. These VNS-EMG artifacts matched well with the VNS generator's set parameters. We conclude that EMG findings must be interpreted with caution in patients with VNS implants and also that EMG may have a possible monitoring value for VNS activity.
PMID: 17139390 [PubMed - indexed for MEDLINE]
13: Neurodegener Dis. 2005;2(3-4):215-9.
Preclinical trials--an update on translational research in ALS.
Ludolph AC, Sperfeld AD.
Department of Neurology, University of Ulm, Ulm, Germany. albert.ludolph@rku.de
Translational research has become a strategy which describes the steps from in vitro experimental therapy, its translation into experimental animals and finally to humans. However, this translation of hypotheses from one of these levels to another faces a number of difficulties which are currently of major interest for the development of therapeutics. In particular, in the previously untreatable motor neuron diseases, the steps from genes to transgenic animals and finally to the patient have proven difficult. High expectations have not met with the transfer of numerous therapies from experimental animals to men; there are many in- and outside the field which already question the value of animal models. It is the opinion of the authors that we should not dismiss the models
before we have not defined generally accepted standards of protocols for therapeutic studies in experimental animals. Only if a generally agreed standardized and validated methodology in mice cannot predict the human response to therapeutics, an animal model should be abandoned. In contrast, the value of translating genetic findings to experimental animals and men is currently shown for motor proteins; in particular the functional impact of dynactin and dynein for the integrity of motor neurons of rodents and men are in the center of
interest.
Publication Types:
Review
PMID: 16909028 [PubMed - indexed for MEDLINE]
Preclinical trials--an update on translational research in ALS.
Ludolph AC, Sperfeld AD.
Department of Neurology, University of Ulm, Ulm, Germany. albert.ludolph@rku.de
Translational research has become a strategy which describes the steps from in vitro experimental therapy, its translation into experimental animals and finally to humans. However, this translation of hypotheses from one of these levels to another faces a number of difficulties which are currently of major interest for the development of therapeutics. In particular, in the previously untreatable motor neuron diseases, the steps from genes to transgenic animals and finally to the patient have proven difficult. High expectations have not met with the transfer of numerous therapies from experimental animals to men; there are many in- and outside the field which already question the value of animal models. It is the opinion of the authors that we should not dismiss the models
before we have not defined generally accepted standards of protocols for therapeutic studies in experimental animals. Only if a generally agreed standardized and validated methodology in mice cannot predict the human response to therapeutics, an animal model should be abandoned. In contrast, the value of translating genetic findings to experimental animals and men is currently shown for motor proteins; in particular the functional impact of dynactin and dynein for the integrity of motor neurons of rodents and men are in the center of
interest.
Publication Types:
Review
PMID: 16909028 [PubMed - indexed for MEDLINE]
12: Neurodegener Dis. 2005;2(3-4):208-14.
Clinical trials in ALS: what did we learn from recent trials in humans?
Meininger V.
ALS National Referral and Coordinating Centre, Hopital Salpetriere, Paris,
France. vincent.meininger@psl.aphp.fr
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease.
No treatment is currently able to stop the disease process. In the absence of new active compounds there is an urgent need to develop new strategies based on the neuroprotective activity of available drugs. ALS is a heterogeneous disease.
To build up these therapeutic trials, we need to have a better understanding of the prognostic factors in this disease. During the Phase IV Rilutek Trial in France, we developed in a large population of patients a prognostic score based on clinical parameters available at the bedside. The most significant variables are vital capacity, spasticity, fasciculations, swallowing, cough and creatininemia. This score proved to be very useful in daily use in the clinic and for planning disease management in ALS as in the design of therapeutic trials. In ALS clinical trials, efficacy can be evaluated using survival or functional parameters. In phase II trials, function remains the most commonly
used. In phase III trials, the gold standard endpoint remains the survival rate
at month 18. We analyzed the most recent ALS trials published in the literature.
This review suggests that in these trials there is a discrepancy between drug
effects on survival versus function. These results suggest that a reappraisal of
strategies to identify therapeutic targets for ALS is required.
Publication Types:
Review
PMID: 16909027 [PubMed - indexed for MEDLINE]
Clinical trials in ALS: what did we learn from recent trials in humans?
Meininger V.
ALS National Referral and Coordinating Centre, Hopital Salpetriere, Paris,
France. vincent.meininger@psl.aphp.fr
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease.
No treatment is currently able to stop the disease process. In the absence of new active compounds there is an urgent need to develop new strategies based on the neuroprotective activity of available drugs. ALS is a heterogeneous disease.
To build up these therapeutic trials, we need to have a better understanding of the prognostic factors in this disease. During the Phase IV Rilutek Trial in France, we developed in a large population of patients a prognostic score based on clinical parameters available at the bedside. The most significant variables are vital capacity, spasticity, fasciculations, swallowing, cough and creatininemia. This score proved to be very useful in daily use in the clinic and for planning disease management in ALS as in the design of therapeutic trials. In ALS clinical trials, efficacy can be evaluated using survival or functional parameters. In phase II trials, function remains the most commonly
used. In phase III trials, the gold standard endpoint remains the survival rate
at month 18. We analyzed the most recent ALS trials published in the literature.
This review suggests that in these trials there is a discrepancy between drug
effects on survival versus function. These results suggest that a reappraisal of
strategies to identify therapeutic targets for ALS is required.
Publication Types:
Review
PMID: 16909027 [PubMed - indexed for MEDLINE]
11: Neurodegener Dis. 2005;2(3-4):202-7.
Hypermetabolism in ALS: correlations with clinical and paraclinical parameters.
Desport JC, Torny F, Lacoste M, Preux PM, Couratier P.
Centre SLA, Service de Neurologie, CHU Dupuytren, France. nutrition@unilim.fr
Despite a reduction in fat-free mass (FFM), a hypermetabolism has been reported with an average of 10% in amyotrophic lateral sclerosis (ALS) patients as compared with a healthy population. The objectives of this study were to confirm the level of hypermetabolism determined by using indirect calorimetry in 168 patients with a probable or a definite ALS and to study correlations with survival. Consecutive evaluations of resting energy expenditure (REE) were performed from diagnosis to the proximity of death in 44 ALS patients. Differences with the calculated value determined a DeltaREE. FFM was given by bioimpedance. At T(1), REE was significantly increased by an average of 14% as
compared with the calculated value. 62.3% of ALS patients were considered as hypermetabolic. REE was correlated in univariate analysis with age, sex, clinical form at onset, presence of a denutrition, weight, FFM, phase angle and ALS Functional Rating Scale (ALSFRS). In multivariate analysis, REE was linked to age and FFM. DeltaREE was correlated in univariate analysis with sex, phase angle and manual muscle testing (MMT). In multivariate analysis, age and sex remained significantly correlated. During progression of ALS, REE levels remained higher than calculated values with a trend to decrease at proximity of death, whereas FFM remained stable. From T(1), survival was linked to MMT, ALSFRS, vital capacity, REE and phase angle. We confirmed the existence of a stable hypermetabolic state in ALS which depends mainly on age, sex and FFM. REE
is a prognostic factor for survival in univariate analysis.
PMID: 16909026 [PubMed - indexed for MEDLINE]
Hypermetabolism in ALS: correlations with clinical and paraclinical parameters.
Desport JC, Torny F, Lacoste M, Preux PM, Couratier P.
Centre SLA, Service de Neurologie, CHU Dupuytren, France. nutrition@unilim.fr
Despite a reduction in fat-free mass (FFM), a hypermetabolism has been reported with an average of 10% in amyotrophic lateral sclerosis (ALS) patients as compared with a healthy population. The objectives of this study were to confirm the level of hypermetabolism determined by using indirect calorimetry in 168 patients with a probable or a definite ALS and to study correlations with survival. Consecutive evaluations of resting energy expenditure (REE) were performed from diagnosis to the proximity of death in 44 ALS patients. Differences with the calculated value determined a DeltaREE. FFM was given by bioimpedance. At T(1), REE was significantly increased by an average of 14% as
compared with the calculated value. 62.3% of ALS patients were considered as hypermetabolic. REE was correlated in univariate analysis with age, sex, clinical form at onset, presence of a denutrition, weight, FFM, phase angle and ALS Functional Rating Scale (ALSFRS). In multivariate analysis, REE was linked to age and FFM. DeltaREE was correlated in univariate analysis with sex, phase angle and manual muscle testing (MMT). In multivariate analysis, age and sex remained significantly correlated. During progression of ALS, REE levels remained higher than calculated values with a trend to decrease at proximity of death, whereas FFM remained stable. From T(1), survival was linked to MMT, ALSFRS, vital capacity, REE and phase angle. We confirmed the existence of a stable hypermetabolic state in ALS which depends mainly on age, sex and FFM. REE
is a prognostic factor for survival in univariate analysis.
PMID: 16909026 [PubMed - indexed for MEDLINE]
10: Neurodegener Dis. 2005;2(3-4):195-201.
Lead exposure as a risk factor for amyotrophic lateral sclerosis.
Kamel F, Umbach DM, Hu H, Munsat TL, Shefner JM, Taylor JA, Sandler DP.
National Institute of Environmental Health Sciences, National Institutes of
Health, Department of Health and Human Services, Research Triangle Park, NC
27709, USA. kamel@mail.nih.gov
BACKGROUND: The etiology of amyotrophic lateral sclerosis (ALS) likely involves
an environmental component. We qualitatively assessed literature on ALS and lead
exposure. Problems of study design make case reports and studies of lead in
blood or tissues difficult to interpret. Most previous case-control studies
found an association of ALS with self-reported occupational exposure to lead,
with increased risks of 2- to >4-fold. However, these results may have been
affected by recall bias. OBJECTIVE: To address inconsistencies among published
reports, we used both lead biomarkers and interview data to assess lead
exposure, and we evaluated the role of genetic susceptibility to lead. METHODS:
We conducted a case-control study in New England in 1993-1996 with 109 ALS cases
and 256 population-based controls. We measured blood and bone lead levels, the
latter using X-ray fluorescence, and interviewed participants regarding sources
of lead exposure. RESULTS: In our study, ALS was associated with self-reported
occupational lead exposure, with a dose response for cumulative days of
exposure. ALS was also associated with blood and bone lead levels, with a
1.9-fold increase in risk for each mug/dl increment in blood lead and a 2.3- to
3.6-fold increase for each doubling of bone lead. A polymorphism in the
delta-aminolevulinic acid dehydratase gene was associated with a 1.9-fold
increase in ALS risk. CONCLUSION: These results, together with previous studies,
suggest that lead exposure plays a role in the etiology of ALS. An increase in
mobilization of lead from bone into blood may play a role in the acute onset of
disease.
Publication Types:
Research Support, N.I.H., Intramural
PMID: 16909025 [PubMed - indexed for MEDLINE]
Lead exposure as a risk factor for amyotrophic lateral sclerosis.
Kamel F, Umbach DM, Hu H, Munsat TL, Shefner JM, Taylor JA, Sandler DP.
National Institute of Environmental Health Sciences, National Institutes of
Health, Department of Health and Human Services, Research Triangle Park, NC
27709, USA. kamel@mail.nih.gov
BACKGROUND: The etiology of amyotrophic lateral sclerosis (ALS) likely involves
an environmental component. We qualitatively assessed literature on ALS and lead
exposure. Problems of study design make case reports and studies of lead in
blood or tissues difficult to interpret. Most previous case-control studies
found an association of ALS with self-reported occupational exposure to lead,
with increased risks of 2- to >4-fold. However, these results may have been
affected by recall bias. OBJECTIVE: To address inconsistencies among published
reports, we used both lead biomarkers and interview data to assess lead
exposure, and we evaluated the role of genetic susceptibility to lead. METHODS:
We conducted a case-control study in New England in 1993-1996 with 109 ALS cases
and 256 population-based controls. We measured blood and bone lead levels, the
latter using X-ray fluorescence, and interviewed participants regarding sources
of lead exposure. RESULTS: In our study, ALS was associated with self-reported
occupational lead exposure, with a dose response for cumulative days of
exposure. ALS was also associated with blood and bone lead levels, with a
1.9-fold increase in risk for each mug/dl increment in blood lead and a 2.3- to
3.6-fold increase for each doubling of bone lead. A polymorphism in the
delta-aminolevulinic acid dehydratase gene was associated with a 1.9-fold
increase in ALS risk. CONCLUSION: These results, together with previous studies,
suggest that lead exposure plays a role in the etiology of ALS. An increase in
mobilization of lead from bone into blood may play a role in the acute onset of
disease.
Publication Types:
Research Support, N.I.H., Intramural
PMID: 16909025 [PubMed - indexed for MEDLINE]
9: Neurodegener Dis. 2005;2(3-4):185-94.
Reticulons as markers of neurological diseases: focus on amyotrophic lateral sclerosis.
Fergani A, Dupuis L, Jokic N, Larmet Y, de Tapia M, Rene F, Loeffler JP, Gonzalez de Aguilar JL.
Laboratoire de Signalisations Moleculaires et Neurodegenerescence, INSERM U-692, Universite Louis Pasteur, Strasbourg, France.
Reticulons (RTNs) are a family of proteins that are primarily associated with the endoplasmic reticulum. In mammals, four genes have been identified and referred as to rtn1, 2, 3 and the neurite outgrowth inhibitor rtn4/nogo. These genes generate multiple isoforms that contain a common C-terminal reticulon homology domain of 150-200 amino-acid residues. The N-terminal regions of RTNs are highly variable, and result from alternative splicing or differential promoter usage. Although widely distributed, the functions of RTNs are still poorly understood. Much interest has been focused on rtn4/nogo because of its activity as a potent inhibitor of axonal growth and repair. In the present study, we update recent knowledge on mammalian RTNs paying special attention to the involvement of these proteins as markers of neurological diseases. We also present recent data concerning RTN expression in amyotrophic lateral sclerosis, a fatal degenerative disorder characterized by loss of upper and lower motor neurons, and muscle atrophy. The rearrangement of RTN expression is regulated not only in suffering skeletal muscle but also preceding the onset of symptoms, and may relate to the disease process.
Publication Types:
Research Support, Non-U.S. Gov't
Reticulons as markers of neurological diseases: focus on amyotrophic lateral sclerosis.
Fergani A, Dupuis L, Jokic N, Larmet Y, de Tapia M, Rene F, Loeffler JP, Gonzalez de Aguilar JL.
Laboratoire de Signalisations Moleculaires et Neurodegenerescence, INSERM U-692, Universite Louis Pasteur, Strasbourg, France.
Reticulons (RTNs) are a family of proteins that are primarily associated with the endoplasmic reticulum. In mammals, four genes have been identified and referred as to rtn1, 2, 3 and the neurite outgrowth inhibitor rtn4/nogo. These genes generate multiple isoforms that contain a common C-terminal reticulon homology domain of 150-200 amino-acid residues. The N-terminal regions of RTNs are highly variable, and result from alternative splicing or differential promoter usage. Although widely distributed, the functions of RTNs are still poorly understood. Much interest has been focused on rtn4/nogo because of its activity as a potent inhibitor of axonal growth and repair. In the present study, we update recent knowledge on mammalian RTNs paying special attention to the involvement of these proteins as markers of neurological diseases. We also present recent data concerning RTN expression in amyotrophic lateral sclerosis, a fatal degenerative disorder characterized by loss of upper and lower motor neurons, and muscle atrophy. The rearrangement of RTN expression is regulated not only in suffering skeletal muscle but also preceding the onset of symptoms, and may relate to the disease process.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16909024 [PubMed - indexed for MEDLINE]
PMID: 16909024 [PubMed - indexed for MEDLINE]
8: Neurodegener Dis. 2005;2(3-4):177-84.
Amyotrophic lateral sclerosis: new developments in diagnostic markers.
Dengler R, von Neuhoff N, Bufler J, Krampfl K, Peschel T, Grosskreutz J.
Department of Neurology, Medical School Hannover, Hannover, Germany.
dengler.reinhard@mh-hannover.de
There is an intensive search for diagnostic markers in amyotrophic lateral
sclerosis (ALS). Protein analysis (proteomics) of the cerebrospinal fluid (CSF)
appears particularly promising using mass spectrometry and 2-D gel
electrophoresis to detect low and high molecular weight proteins, respectively.
It is open whether protein changes specific for ALS will be found. This also
holds true for inflammatory proteins such as the cytokine monocyte
chemoattractant protein-1 which has been detected in CSF in ALS and for other
cytokines such as interleukin-1beta. Increases of the protein Nogo A and B in
muscle tissue and decreases of the growth factor vascular endothelial growth
factor in blood may also be useful for monitoring the course of ALS. Clinical
neurophysiology provides markers for upper and lower motor neuron damage. A very
sensitive method to detect early upper motor neuron involvement is the
transcranial magnetic stimulation modification 'triple stimulation technique'
which can show significant changes in patients without clinical upper motor
neuron signs. The loss of lower motor neurons can be closely monitored by MUNE
techniques (motor unit number estimate). In modern imaging, the MRI technique
DTI (diffusion tensor imaging) has the greatest diagnostic potential for ALS. It
can separate between normal and ALS in group comparisons and may be improved to
be diagnostic in individual patients. Voxel-based morphometry can reliably
demonstrate regional cortical atrophy in motor areas and beyond although it is
not appropriate for use in individual patients.
Publication Types:
Review
PMID: 16909023 [PubMed - indexed for MEDLINE]
7: Neurodegener Dis. 2005;2(3-4):166-76.
Implications for the kynurenine pathway and quinolinic acid in amyotrophic
lateral sclerosis.
Guillemin GJ, Meininger V, Brew BJ.
Centre for Immunology and University of New South Wales, School of Medicine and
School of Medical Sciences, Sydney, Australia. g.guillemin@cfi.unsw.edu.au
The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading
to production of several neurobiologically active molecules. Among them is the
excitotoxin quinolinic acid (QUIN) that is known to be involved in the
pathogenesis of several major inflammatory neurological diseases. In amyotrophic
lateral sclerosis (ALS) degeneration of motor neurons is associated with a
chronic and local inflammation (presence of activated microglia and astrocytes).
There is emerging evidence that the KP is important in ALS. Recently, we
demonstrated that QUIN is significantly increased in serum and CSF of ALS
patients. Moreover, most of the factors associated with QUIN toxicity are found
in ALS, implying that QUIN may play a substantial role in the neuropathogenesis
of ALS. This review details the potential role the KP has in ALS and advances a
testable hypothetical model.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16909022 [PubMed - indexed for MEDLINE]
6: Neurodegener Dis. 2005;2(3-4):147-59.
Excitotoxicity and amyotrophic lateral sclerosis.
Van Damme P, Dewil M, Robberecht W, Van Den Bosch L.
Neurobiology, Campus Gasthuisberg, Leuven, Belgium.
Since its description by Charcot more than 130 years ago, the pathogenesis of selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains unsolved. Over the years, many pathogenic mechanisms have been proposed. Amongst others these include: oxidative stress, excitotoxicity, aggregate formation, inflammation, growth factor deficiency and neurofilament disorganization. This multitude of contributing factors indicates that ALS is a complex disease and also suggests that ALS is a multifactorial disorder. Excitotoxicity is not the newest and most spectacular hypothesis in the ALS field, but it is undoubtedly one of the most robust pathogenic mechanisms supported by an impressive amount of evidence. Moreover, the therapeutic efficacy of riluzole, the only drug proven to slow disease progression in ALS, is most likely related to its anti-excitotoxic properties. In this review, we will give an overview of the arguments in favor of the involvement of excitotoxicity in ALS and of the possible mechanisms leading to motor neuron death. We will also summarize the intrinsic properties of motor neurons that
render these cells particularly vulnerable to excitotoxicity and could explain the selective vulnerability of motor neurons in ALS. All this information could help to develop new and better therapeutic strategies that could protect motor neurons from excitotoxicity.
Publication Types:
Review
PMID: 16909020 [PubMed - indexed for MEDLINE]
Excitotoxicity and amyotrophic lateral sclerosis.
Van Damme P, Dewil M, Robberecht W, Van Den Bosch L.
Neurobiology, Campus Gasthuisberg, Leuven, Belgium.
Since its description by Charcot more than 130 years ago, the pathogenesis of selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains unsolved. Over the years, many pathogenic mechanisms have been proposed. Amongst others these include: oxidative stress, excitotoxicity, aggregate formation, inflammation, growth factor deficiency and neurofilament disorganization. This multitude of contributing factors indicates that ALS is a complex disease and also suggests that ALS is a multifactorial disorder. Excitotoxicity is not the newest and most spectacular hypothesis in the ALS field, but it is undoubtedly one of the most robust pathogenic mechanisms supported by an impressive amount of evidence. Moreover, the therapeutic efficacy of riluzole, the only drug proven to slow disease progression in ALS, is most likely related to its anti-excitotoxic properties. In this review, we will give an overview of the arguments in favor of the involvement of excitotoxicity in ALS and of the possible mechanisms leading to motor neuron death. We will also summarize the intrinsic properties of motor neurons that
render these cells particularly vulnerable to excitotoxicity and could explain the selective vulnerability of motor neurons in ALS. All this information could help to develop new and better therapeutic strategies that could protect motor neurons from excitotoxicity.
Publication Types:
Review
PMID: 16909020 [PubMed - indexed for MEDLINE]
5: Neurodegener Dis. 2005;2(3-4):139-46.
Complexity of astrocyte-motor neuron interactions in amyotrophic lateral
sclerosis.
Pehar M, Vargas MR, Cassina P, Barbeito AG, Beckman JS, Barbeito L.
Departamento de Neurobiologia Celular y Molecular, Instituto de Investigaciones
Biologicas Clemente Estable, Montevideo, Uruguay.
Neurons and surrounding glial cells compose a highly specialized functional unit. In amyotrophic lateral sclerosis (ALS) astrocytes interact with motor neurons in a complex manner to modulate neuronal survival. Experiments using chimeric mice expressing ALS-linked mutations to Cu,Zn superoxide dismutase (SOD-1) suggest a critical modulation exerted by neighboring non-neuronal cell types on disease phenotype. When perturbed by primary neuronal damage, e.g. expression of SOD-1 mutations, neurons can signal astrocytes to proliferate and become reactive. Fibroblast growth factor-1 (FGF-1) can be released by motor neurons in response to damage to induce astrocyte activation by signaling through the receptor FGFR1. FGF-1 stimulates nerve growth factor (NGF)
expression and secretion, as well as activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. Nrf2 leads to the expression of antioxidant and cytoprotective enzymes such as heme oxygenase-1 and a group of enzymes involved in glutathione metabolism that prevent motor neuron degeneration. However, prolonged stimulation with FGF-1 or SOD-mediated oxidative stress in astrocytes may disrupt the normal neuron-glia interactions and lead to progressive neuronal degeneration. The re-expression of p75 neurotrophin receptor and neuronal NOS in motor neurons in parallel with increased NGF secretion by reactive astrocytes may be a mechanism to eliminate critically damaged neurons. Consequently, astrocyte activation in ALS may have a complex pathogenic role.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16909019 [PubMed - indexed for MEDLINE]
Complexity of astrocyte-motor neuron interactions in amyotrophic lateral
sclerosis.
Pehar M, Vargas MR, Cassina P, Barbeito AG, Beckman JS, Barbeito L.
Departamento de Neurobiologia Celular y Molecular, Instituto de Investigaciones
Biologicas Clemente Estable, Montevideo, Uruguay.
Neurons and surrounding glial cells compose a highly specialized functional unit. In amyotrophic lateral sclerosis (ALS) astrocytes interact with motor neurons in a complex manner to modulate neuronal survival. Experiments using chimeric mice expressing ALS-linked mutations to Cu,Zn superoxide dismutase (SOD-1) suggest a critical modulation exerted by neighboring non-neuronal cell types on disease phenotype. When perturbed by primary neuronal damage, e.g. expression of SOD-1 mutations, neurons can signal astrocytes to proliferate and become reactive. Fibroblast growth factor-1 (FGF-1) can be released by motor neurons in response to damage to induce astrocyte activation by signaling through the receptor FGFR1. FGF-1 stimulates nerve growth factor (NGF)
expression and secretion, as well as activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. Nrf2 leads to the expression of antioxidant and cytoprotective enzymes such as heme oxygenase-1 and a group of enzymes involved in glutathione metabolism that prevent motor neuron degeneration. However, prolonged stimulation with FGF-1 or SOD-mediated oxidative stress in astrocytes may disrupt the normal neuron-glia interactions and lead to progressive neuronal degeneration. The re-expression of p75 neurotrophin receptor and neuronal NOS in motor neurons in parallel with increased NGF secretion by reactive astrocytes may be a mechanism to eliminate critically damaged neurons. Consequently, astrocyte activation in ALS may have a complex pathogenic role.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16909019 [PubMed - indexed for MEDLINE]
4: Neurodegener Dis. 2005;2(3-4):135-8.
Anti-ALS activity of alsin, the product of the ALS2 gene, and activity-dependent
neurotrophic factor.
Matsuoka M, Nishimoto I.
Department of Pharmacology, Keio University School of Medicine, Tokyo, Japan.
sakimatu@sc.itc.keio.ac.jp
Amyotrophic lateral sclerosis (ALS) is an incurable degenerative motoneuronal disease. The complete suppression of motoneuronal death is the ultimate goal of ALS therapy. Two new prosurvival pathways have been recently demonstrated to antagonize neurotoxicity by familial ALS-linked mutant Cu/Zn-superoxide dismutase (FSOD1). Alsin, the product of the recently cloned ALS-causative gene, the ALS2 gene, is linked to a Rac1/phosphatidylinositol-3 kinase/Akt3 pathway that specifically suppresses motoneuronal death induced by FSOD1. Activity-dependent neurotrophic factor, originally identified as an anti-Alzheimer neurotrophic factor, has been shown to suppress motoneuronal death by FSOD1 through a prosurvival pathway mediated by Ca(2+)/calmodulin-dependent protein kinase IV. Activation of these novel anti-ALS pathways may serve as a promising way to suppress ALS-related motoneuronal cell death.
Publication Types:
Review
PMID: 16909018 [PubMed - indexed for MEDLINE]
Anti-ALS activity of alsin, the product of the ALS2 gene, and activity-dependent
neurotrophic factor.
Matsuoka M, Nishimoto I.
Department of Pharmacology, Keio University School of Medicine, Tokyo, Japan.
sakimatu@sc.itc.keio.ac.jp
Amyotrophic lateral sclerosis (ALS) is an incurable degenerative motoneuronal disease. The complete suppression of motoneuronal death is the ultimate goal of ALS therapy. Two new prosurvival pathways have been recently demonstrated to antagonize neurotoxicity by familial ALS-linked mutant Cu/Zn-superoxide dismutase (FSOD1). Alsin, the product of the recently cloned ALS-causative gene, the ALS2 gene, is linked to a Rac1/phosphatidylinositol-3 kinase/Akt3 pathway that specifically suppresses motoneuronal death induced by FSOD1. Activity-dependent neurotrophic factor, originally identified as an anti-Alzheimer neurotrophic factor, has been shown to suppress motoneuronal death by FSOD1 through a prosurvival pathway mediated by Ca(2+)/calmodulin-dependent protein kinase IV. Activation of these novel anti-ALS pathways may serve as a promising way to suppress ALS-related motoneuronal cell death.
Publication Types:
Review
PMID: 16909018 [PubMed - indexed for MEDLINE]
3: Neurodegener Dis. 2005;2(3-4):128-34.
Inter- and intracellular signaling in amyotrophic lateral sclerosis: role of p38
mitogen-activated protein kinase.
Bendotti C, Bao Cutrona M, Cheroni C, Grignaschi G, Lo Coco D, Peviani M,
Tortarolo M, Veglianese P, Zennaro E.
Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di
Ricerche Farmacologiche 'Mario Negri', Milano, Italy. Bendotti@marionegri.it
The pathogenetic processes underlying the selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are complex and still not completely understood even in the cases of inherited disease caused by mutations in the Cu/Zn superoxide dismutase-dependent (SOD1) gene. Recent evidence supports the view that ALS is not a cell-autonomous disease and that glial-neuron cross-talk, throughout cytokines and other toxic factors like the nitric oxide and superoxide, is a crucial determinant for the induction of motor neuron death. This cell-cell interaction may determine the progression of the disease through processes that are likely independent of the initial trigger and that may
converge on the activation of intracellular death pathways in the motor neurons.
In this review we provide support to the hypothesis that aberrant expression and activity of p38 mitogen protein-activated kinases cascade (p38MAPK) in motor neurons and glial cells may play a role in the development and progression of ALS. Increased activation of p38MAPK may phosphorylate neuron-specific substrates altering their physiological properties and it may turn on responsive genes leading to neurotoxicity.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16909017 [PubMed - indexed for MEDLINE]
2: Neurodegener Dis. 2005;2(3-4):115-27.
Mutant SOD1 instability: implications for toxicity in amyotrophic lateral
sclerosis.
Tiwari A, Hayward LJ.
Department of Neurology, University of Massachusetts Medical School, Worcester,
01655, USA.
The biological basis of preferential motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains incompletely understood, and effective therapies to prevent the lethal consequences of this disorder are not yet available. Since 1993, more than 100 mutant variants of the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) have been identified in familial ALS. Many studies have sought to distinguish abnormal properties shared by these proteins that may contribute to their toxic effects and cause age-dependent motor neuron loss. Complex networks of cellular interactions and changes associated with aging may link mutant SOD1s and other stresses to motor neuron death in ALS. Our laboratory and collaborators have compared physicochemical properties of biologically metallated wild-type and mutant SOD1 proteins to discern specific vulnerabilities that may be relevant to the mutant toxicity in vivo. X-ray crystal structures obtained from metallated 'wild-type-like' (WTL) SOD1 mutants, which retain the ability to bind copper and zinc and exhibit normal specific activity, indicate a native-like structure with only subtle changes to the backbone fold. In contrast, a group of 'metal-binding region' (MBR) SOD1 mutants that are deficient in copper and zinc exhibit severe thermal destabilization and structural disorder of conserved loops near the metal-binding sites. A growing body of evidence highlights specific stresses in vivo that may perturb well-folded, metallated SOD1 variants and thereby favor an increased burden of partially unfolded, metal-deficient species. For example, WTL SOD1 mutants are more susceptible than wild-type SOD1 to reduction of the intrasubunit disulfide bond between Cys-57 and Cys-146 at physiological pH and temperature. This bond anchors the disulfide loop to the SOD1 beta-barrel and helps to maintain the dimeric configuration of the protein. Cleavage of the disulfide linkage renders the well-folded WTL mutants vulnerable to metal loss and monomerization such that they may resemble the destabilized and locally misfolded MBR mutant species. SOD1 proteins with disordered loops or monomeric structure are expected to be more susceptible to aberrant self-association or detrimental interactions
with other cellular constituents. The challenge for future investigations is to relate these abnormal properties of partially unfolded SOD1 to specific mechanisms of toxicity in motor neurons, supporting cells, or target tissues.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16909016 [PubMed - indexed for MEDLINE]
Mutant SOD1 instability: implications for toxicity in amyotrophic lateral
sclerosis.
Tiwari A, Hayward LJ.
Department of Neurology, University of Massachusetts Medical School, Worcester,
01655, USA.
The biological basis of preferential motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains incompletely understood, and effective therapies to prevent the lethal consequences of this disorder are not yet available. Since 1993, more than 100 mutant variants of the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) have been identified in familial ALS. Many studies have sought to distinguish abnormal properties shared by these proteins that may contribute to their toxic effects and cause age-dependent motor neuron loss. Complex networks of cellular interactions and changes associated with aging may link mutant SOD1s and other stresses to motor neuron death in ALS. Our laboratory and collaborators have compared physicochemical properties of biologically metallated wild-type and mutant SOD1 proteins to discern specific vulnerabilities that may be relevant to the mutant toxicity in vivo. X-ray crystal structures obtained from metallated 'wild-type-like' (WTL) SOD1 mutants, which retain the ability to bind copper and zinc and exhibit normal specific activity, indicate a native-like structure with only subtle changes to the backbone fold. In contrast, a group of 'metal-binding region' (MBR) SOD1 mutants that are deficient in copper and zinc exhibit severe thermal destabilization and structural disorder of conserved loops near the metal-binding sites. A growing body of evidence highlights specific stresses in vivo that may perturb well-folded, metallated SOD1 variants and thereby favor an increased burden of partially unfolded, metal-deficient species. For example, WTL SOD1 mutants are more susceptible than wild-type SOD1 to reduction of the intrasubunit disulfide bond between Cys-57 and Cys-146 at physiological pH and temperature. This bond anchors the disulfide loop to the SOD1 beta-barrel and helps to maintain the dimeric configuration of the protein. Cleavage of the disulfide linkage renders the well-folded WTL mutants vulnerable to metal loss and monomerization such that they may resemble the destabilized and locally misfolded MBR mutant species. SOD1 proteins with disordered loops or monomeric structure are expected to be more susceptible to aberrant self-association or detrimental interactions
with other cellular constituents. The challenge for future investigations is to relate these abnormal properties of partially unfolded SOD1 to specific mechanisms of toxicity in motor neurons, supporting cells, or target tissues.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16909016 [PubMed - indexed for MEDLINE]
1: Neurodegener Dis. 2005;2(5):246-54.
Celastrol blocks neuronal cell death and extends life in transgenic mouse model
of amyotrophic lateral sclerosis.
Kiaei M, Kipiani K, Petri S, Chen J, Calingasan NY, Beal MF.
Department of Neurology and Neuroscience, Weill Medical College of Cornell
University, New York-Presbyterian Hospital, New York, NY 10021, USA.
mak2026@med.cornell.edu
There is substantial evidence that both inflammation and oxidative damage contribute to the pathogenesis of motor neuron degeneration in the G93A SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS). Celastrol is a natural product from Southern China, which exerts potent anti-inflammatory and antioxidative effects. It also acts potently to increase expression of heat shock proteins including HSP70. We administered it in the diet to G93A SOD1 mice starting at 30 days of age. Celastrol treatment significantly improved weight loss, motor performance and delayed the onset of ALS. Survival of
celastrol-treated G93A mice increased by 9.4% and 13% for 2 mg/kg/day and 8 mg/kg/day doses, respectively. Cell counts of lumbar spinal cord neurons confirmed a protective effect, i.e. 30% increase in neuronal number in the lumbar spinal cords of celastrol-treated animals. Celastrol treatment reduced TNF-alpha, iNOS, CD40, and GFAP immunoreactivity in the lumbar spinal cord sections of celastrol-treated G93A mice compared to untreated G93A mice. TNF-alpha immunoreactivity co-localized with SMI-32 (neuronal marker) and GFAP (astrocyte marker). HSP70 immunoreactivity was increased in lumbar spinal cord neurons of celastrol-treated G93A mice. Celastrol has been widely used in treating inflammatory diseases in man, and is well tolerated; therefore, it may be a promising therapeutic candidate for the treatment of human ALS. Copyright 2005 S. Karger AG, Basel.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16909005 [PubMed - indexed for MEDLINE]
Celastrol blocks neuronal cell death and extends life in transgenic mouse model
of amyotrophic lateral sclerosis.
Kiaei M, Kipiani K, Petri S, Chen J, Calingasan NY, Beal MF.
Department of Neurology and Neuroscience, Weill Medical College of Cornell
University, New York-Presbyterian Hospital, New York, NY 10021, USA.
mak2026@med.cornell.edu
There is substantial evidence that both inflammation and oxidative damage contribute to the pathogenesis of motor neuron degeneration in the G93A SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS). Celastrol is a natural product from Southern China, which exerts potent anti-inflammatory and antioxidative effects. It also acts potently to increase expression of heat shock proteins including HSP70. We administered it in the diet to G93A SOD1 mice starting at 30 days of age. Celastrol treatment significantly improved weight loss, motor performance and delayed the onset of ALS. Survival of
celastrol-treated G93A mice increased by 9.4% and 13% for 2 mg/kg/day and 8 mg/kg/day doses, respectively. Cell counts of lumbar spinal cord neurons confirmed a protective effect, i.e. 30% increase in neuronal number in the lumbar spinal cords of celastrol-treated animals. Celastrol treatment reduced TNF-alpha, iNOS, CD40, and GFAP immunoreactivity in the lumbar spinal cord sections of celastrol-treated G93A mice compared to untreated G93A mice. TNF-alpha immunoreactivity co-localized with SMI-32 (neuronal marker) and GFAP (astrocyte marker). HSP70 immunoreactivity was increased in lumbar spinal cord neurons of celastrol-treated G93A mice. Celastrol has been widely used in treating inflammatory diseases in man, and is well tolerated; therefore, it may be a promising therapeutic candidate for the treatment of human ALS. Copyright 2005 S. Karger AG, Basel.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16909005 [PubMed - indexed for MEDLINE]
