25: J Neurol Neurosurg Psychiatry. 2006 Nov;77(11):1253-5. Epub 2006 Jul 11.
Cerebral degeneration predicts survival in amyotrophic lateral sclerosis.
Kalra S, Vitale A, Cashman NR, Genge A, Arnold DL.
Department of Medicine, Division of Neurology, University of Alberta, Edmonton,
Alberta, Canada. sanjay.kalra@ualberta.ca
OBJECTIVE: To determine the relationship of cerebral degeneration with survival in amyotrophic lateral sclerosis (ALS). METHODS: Patients with probable or definite ALS underwent magnetic resonance spectroscopic imaging (MRSI) of the brain between July 1996 and May 2002, and were followed prospectively until March 2004. Creatine (Cr), choline (Cho) and the neuronal marker N-acetylaspartate (NAA) were quantified as ratios in the motor cortex. RESULTS: In 63 patients compared with 18 healthy people, NAA/Cho was reduced by 13% (p<0.001), NAA/Cr was reduced by 5% (p = 0.01) and Cho/Cr was increased by 8% (p = 0.01). NAA/Cho was used for survival analysis, given its larger effect size and superior test accuracy (a sensitivity of 67% and a specificity of 83%). Median survival after MRSI was 24 months. Multivariate analysis showed reduced survival for lower NAA/Cho (hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.08 to 0.72, p = 0.01), older age (HR 1.03, 95% CI 1.00 to 1.06, p = 0.04) and shorter symptom duration (HR 0.96, 95% CI 0.93 to 0.99, p = 0.01). Patients with NAA/Cho <2.11 had a reduced survival of 19.4 v 31.9 months (HR 2.05, 95% CI 1.12 to 4.03, p = 0.02). CONCLUSIONS: Cerebral degeneration is predictive of reduced survival in ALS.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16835288 [PubMed - indexed for MEDLINE]
Cerebral degeneration predicts survival in amyotrophic lateral sclerosis.
Kalra S, Vitale A, Cashman NR, Genge A, Arnold DL.
Department of Medicine, Division of Neurology, University of Alberta, Edmonton,
Alberta, Canada. sanjay.kalra@ualberta.ca
OBJECTIVE: To determine the relationship of cerebral degeneration with survival in amyotrophic lateral sclerosis (ALS). METHODS: Patients with probable or definite ALS underwent magnetic resonance spectroscopic imaging (MRSI) of the brain between July 1996 and May 2002, and were followed prospectively until March 2004. Creatine (Cr), choline (Cho) and the neuronal marker N-acetylaspartate (NAA) were quantified as ratios in the motor cortex. RESULTS: In 63 patients compared with 18 healthy people, NAA/Cho was reduced by 13% (p<0.001), NAA/Cr was reduced by 5% (p = 0.01) and Cho/Cr was increased by 8% (p = 0.01). NAA/Cho was used for survival analysis, given its larger effect size and superior test accuracy (a sensitivity of 67% and a specificity of 83%). Median survival after MRSI was 24 months. Multivariate analysis showed reduced survival for lower NAA/Cho (hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.08 to 0.72, p = 0.01), older age (HR 1.03, 95% CI 1.00 to 1.06, p = 0.04) and shorter symptom duration (HR 0.96, 95% CI 0.93 to 0.99, p = 0.01). Patients with NAA/Cho <2.11 had a reduced survival of 19.4 v 31.9 months (HR 2.05, 95% CI 1.12 to 4.03, p = 0.02). CONCLUSIONS: Cerebral degeneration is predictive of reduced survival in ALS.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16835288 [PubMed - indexed for MEDLINE]
24: Rheumatology (Oxford). 2006 Nov;45(11):1445-6. Epub 2006 Jul 28.
Is TNFalpha really a good therapeutic target in motoneuronal degeneration? A case of amyotrophic lateral sclerosis in a patient with RA receiving infliximab.
Dziadzio M, Reddy V, Rahman S, Mummery C, Keat A.
Publication Types:
Case Reports
Letter
PMID: 16877458 [PubMed - indexed for MEDLINE]
Is TNFalpha really a good therapeutic target in motoneuronal degeneration? A case of amyotrophic lateral sclerosis in a patient with RA receiving infliximab.
Dziadzio M, Reddy V, Rahman S, Mummery C, Keat A.
Publication Types:
Case Reports
Letter
PMID: 16877458 [PubMed - indexed for MEDLINE]
23: Muscle Nerve. 2006 Nov;34(5):595-602.
Assessing neuromuscular disease with multifrequency electrical impedance myography.
Esper GJ, Shiffman CA, Aaron R, Lee KS, Rutkove SB.
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical
School, TCC-810, Boston, Massachusetts 02215, USA.
Electrical impedance myography (EIM) is a noninvasive technique for neuromuscular assessment in which low-intensity alternating current is applied to a muscle and the consequent surface voltage patterns are evaluated. Previous work using a single frequency of 50 kHZ has demonstrated quantitative correlation of EIM parameters with disease status. In this investigation we examined the use of multifrequency EIM, studying a prototypical neurogenic disease (amyotrophic lateral sclerosis, ALS) and myopathic disorder (inflammatory myopathy, IM). Eleven ALS patients, 7 IM patients, and 46 normal
subjects participated in the study. Although disease-specific patterns were not identified such that IM could be differentiated from ALS, impedance vs. frequency patterns for diseased subjects differed substantially from those of the age-matched normal subjects, with the greatest alterations occurring in the most severe cases. Multifrequency EIM may be well-suited to serve as an easily applied technique to assess disease severity in a variety of neuromuscular conditions.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16881067 [PubMed - indexed for MEDLINE]
22: Muscle Nerve. 2006 Nov;34(5):603-7.
Motor unit number estimation predicts disease onset and survival in a transgenic mouse model of amyotrophic lateral sclerosis.
Shefner JM, Cudkowicz M, Brown RH Jr.
Department of Neurology, Upstate Medical University, Syracuse, New York 13210,
USA. shefnerj@upstate.edu
Motor unit number estimation (MUNE) has proved useful in predicting rate of progression and survival in patients with amyotrophic lateral sclerosis (ALS).
In animal models, it has demonstrated physiological effects of experimental medications that were not evident behaviorally. We sought to determine more specifically what aspects of function and survival that MUNE could predict in the G93A transgenic mouse model of ALS. Transgenic mice were examined in two distinct treatment studies, neither of which showed an effect of drug on survival, behavioral measures, or MUNE. MUNE was performed using a modification of the incremental stimulation method by stimulating the sciatic nerve at the sciatic notch, and recording with a circumferential surface electrode around the ipsilateral distal hindlimb. Both limbs were studied and the results averaged.
MUNE was performed longitudinally on all animals from near onset to premorbid state. Each study was evaluated separately. For both studies, MUNE at initial study correlated significantly with behavioral determination of disease onset, and MUNE slope from initial to final study correlated significantly with disease duration, as measured from onset to time of death. However, the final MUNE value did not correlate with survival. Thus, in two studies involving animals with quite different disease courses, initial MUNE effectively predicted symptom onset and MUNE slope predicted survival. This suggests that MUNE has potential efficacy as a useful functional outcome measure in both animal and human studies
of ALS.
PMID: 16892429 [PubMed - indexed for MEDLINE]
21: Suppl Clin Neurophysiol. 2006;59:35-42.
Optimal methods of stimulus presentation and frequency analysis in P300-based brain-computer interfaces for patients with severe motor impairment.
Neshige R, Murayama N, Tanoue K, Kurokawa H, Igasaki T.
Neshige Neurological Clinic, 38-17 Tyuou-machi, Kurume, Fukuoka, Japan.
neshiryu@yahoo.co.jp
Publication Types:
Controlled Clinical Trial
PMID: 16893090 [PubMed - indexed for MEDLINE]
20: Suppl Clin Neurophysiol. 2006;59:327-32.
Transcranial magnetic stimulation for upper motor neuron involvement in amyotrophic lateral sclerosis (ALS).
Mitsumoto H, Floyd A, Tang MX, Kaufmann P, Battista V, Hristova A, Pullman SL.
Department of Neurology, Columbia University, New York, NY 10032, USA.
hm246@columbia.edu
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16893129 [PubMed - indexed for MEDLINE]
Transcranial magnetic stimulation for upper motor neuron involvement in amyotrophic lateral sclerosis (ALS).
Mitsumoto H, Floyd A, Tang MX, Kaufmann P, Battista V, Hristova A, Pullman SL.
Department of Neurology, Columbia University, New York, NY 10032, USA.
hm246@columbia.edu
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16893129 [PubMed - indexed for MEDLINE]
19: Neurology. 2006 Nov 28;67(10):1748-51.
Selecting promising ALS therapies in clinical trials.
* Cheung YK,
* Gordon PH,
* Levin B.
Department of Biostatistics, Columbia University Mailman School of Public Health, New York, NY 10032, USA. yc632@columbia.edu
Riluzole is the only approved medication that extends survival for patients with amyotrophic lateral sclerosis (ALS). While other potential neuroprotective agents have been evaluated in randomized clinical trials, none has shown unequivocal success and none has been approved by regulatory agencies. Few symptomatic therapies have been tested in ALS. Effectiveness for drugs with modest benefit can be established only through large phase III randomized clinical trials. With numerous potential agents but limited resources, priority should be given to agents that show promise in phase II trials before proceeding to evaluation in phase III trials. In this article, we review drug development in early phase ALS trials and introduce novel designs. First, to maximize the therapeutic potential of the test medication, we need to identify the highest dose that produces a tolerable level of side effects. Second, candidate treatments should be ranked by conducting randomized selection trials between competing new treatments. The selection paradigm adopts a statistical viewpoint different from the hypothesis testing framework in conventional trials. We exemplify this approach by describing a group-sequential selection design developed for a phase II, randomized, multicenter trial of two combination treatments in patients with ALS, and illustrate the sample size reduction from a conventional trial.
PMID: 17130405 [PubMed - indexed for MEDLINE]
18: Neurology. 2006 Nov 28;67(10):1827-32. Substance via MeSH,
The value of database controls in pilot or futility studies in ALS.
* Czaplinski A,
* Haverkamp LJ,
* Yen AA,
* Simpson EP,
* Lai EC,
* Appel SH.
Department of Neurology, University of Basel, Basel, Switzerland.
OBJECTIVE: To evaluate the use and reliability of database controls in place of a placebo group in pilot or "futility" ALS trials. METHODS: We compared the rates of disease progression in the placebo arm of the clinical phase III US Insulin-like Growth Factor-I Trial (n = 90) with the rates of disease progression of 207 patients with ALS selected from 1,600 ALS database patients using the same inclusion criteria. RESULTS: The mean rates of change in the Appel ALS (AALS) score were nearly identical in the placebo group (4.70 points/month) and in the database group (4.79 points/month). In addition, there was no significant difference in the median time to achieving a 20-point progression in AALS score: 143 days for database match vs 146 days for the placebo group (log rank p = 0.88). Furthermore, in the multivariate Cox analysis, both the rate at which the disease had progressed prior to first exam (preslope) (p < 0.001) and first exam AALS total score (p = 0.01) were shown to be covariates of subsequent rate of disease progression. CONCLUSION: The similarity in disease progression between placebo arm of clinical phase III trial and matched database group suggests the value of historical databases in futility trials. However, the proposed study design requires appropriate matching of study patients with database controls. Based on our results, we suggest matching by stage of the disease and rate of clinical decline in a contemporaneous ALS population.
PMID: 17130417 [PubMed - indexed for MEDLINE]
The value of database controls in pilot or futility studies in ALS.
* Czaplinski A,
* Haverkamp LJ,
* Yen AA,
* Simpson EP,
* Lai EC,
* Appel SH.
Department of Neurology, University of Basel, Basel, Switzerland.
OBJECTIVE: To evaluate the use and reliability of database controls in place of a placebo group in pilot or "futility" ALS trials. METHODS: We compared the rates of disease progression in the placebo arm of the clinical phase III US Insulin-like Growth Factor-I Trial (n = 90) with the rates of disease progression of 207 patients with ALS selected from 1,600 ALS database patients using the same inclusion criteria. RESULTS: The mean rates of change in the Appel ALS (AALS) score were nearly identical in the placebo group (4.70 points/month) and in the database group (4.79 points/month). In addition, there was no significant difference in the median time to achieving a 20-point progression in AALS score: 143 days for database match vs 146 days for the placebo group (log rank p = 0.88). Furthermore, in the multivariate Cox analysis, both the rate at which the disease had progressed prior to first exam (preslope) (p < 0.001) and first exam AALS total score (p = 0.01) were shown to be covariates of subsequent rate of disease progression. CONCLUSION: The similarity in disease progression between placebo arm of clinical phase III trial and matched database group suggests the value of historical databases in futility trials. However, the proposed study design requires appropriate matching of study patients with database controls. Based on our results, we suggest matching by stage of the disease and rate of clinical decline in a contemporaneous ALS population.
PMID: 17130417 [PubMed - indexed for MEDLINE]
17: Neurology. 2006 Nov 28;67(10):1833-6. Substance via MeSH
Elevated serum angiogenin levels in ALS.
* Cronin S,
* Greenway MJ,
* Ennis S,
* Kieran D,
* Green A,
* Prehn JH,
* Hardiman O.
Department of Physiology, Royal College of Surgeons in Ireland, Ireland. scronin@rcsi.ie
BACKGROUND: The role of hypoxia responsive genes in the pathogenesis of ALS was first suggested when deletions of the hypoxia-responsive element of vascular endothelial growth factor (VEGF) promoter caused a motor neuron disease phenotype in mice. The discovery of ALS-associated mutations in ANG, a hypoxia responsive gene coding for the protein angiogenin, has further supported this pathogenic mechanism in human ALS. In endothelium, angiogenin can regulate expression of VEGF. To date, the patterns of serum angiogenin expression among patients with ALS have not been assessed. METHODS: Serum angiogenin and VEGF levels were quantified at diagnosis in 79 patients with definite or probable ALS and 72 healthy controls, using a quantitative sandwich enzyme-linked immunoassay. RESULTS: Patients with ALS exhibited higher serum angiogenin (p = 0.006) but not VEGF (p = 0.55) levels than matched control subjects. Subgroup analysis showed a greater elevation in angiogenin levels for spinal- (p < 0.001) than bulbar- (p = 0.11) onset ALS vs controls. At 12 months, angiogenin levels remained elevated. No correlation was noted between angiogenin and VEGF levels (r = -0.08, p = 0.49) in ALS patient serum. CONCLUSION: These data suggest a modest elevation in serum angiogenin in ALS at diagnosis. Further investigation will be required to assess the utility of serum angiogenin as a biomarker for ALS and as a predictor of disease progression.
PMID: 17130418 [PubMed - indexed for MEDLINE]
Elevated serum angiogenin levels in ALS.
* Cronin S,
* Greenway MJ,
* Ennis S,
* Kieran D,
* Green A,
* Prehn JH,
* Hardiman O.
Department of Physiology, Royal College of Surgeons in Ireland, Ireland. scronin@rcsi.ie
BACKGROUND: The role of hypoxia responsive genes in the pathogenesis of ALS was first suggested when deletions of the hypoxia-responsive element of vascular endothelial growth factor (VEGF) promoter caused a motor neuron disease phenotype in mice. The discovery of ALS-associated mutations in ANG, a hypoxia responsive gene coding for the protein angiogenin, has further supported this pathogenic mechanism in human ALS. In endothelium, angiogenin can regulate expression of VEGF. To date, the patterns of serum angiogenin expression among patients with ALS have not been assessed. METHODS: Serum angiogenin and VEGF levels were quantified at diagnosis in 79 patients with definite or probable ALS and 72 healthy controls, using a quantitative sandwich enzyme-linked immunoassay. RESULTS: Patients with ALS exhibited higher serum angiogenin (p = 0.006) but not VEGF (p = 0.55) levels than matched control subjects. Subgroup analysis showed a greater elevation in angiogenin levels for spinal- (p < 0.001) than bulbar- (p = 0.11) onset ALS vs controls. At 12 months, angiogenin levels remained elevated. No correlation was noted between angiogenin and VEGF levels (r = -0.08, p = 0.49) in ALS patient serum. CONCLUSION: These data suggest a modest elevation in serum angiogenin in ALS at diagnosis. Further investigation will be required to assess the utility of serum angiogenin as a biomarker for ALS and as a predictor of disease progression.
PMID: 17130418 [PubMed - indexed for MEDLINE]
16: Neurology. 2006 Nov 28;67(10):1894-5. Compound via MeSH, Substance via MeSH,
Motor neuron disorder simulating ALS induced by chronic inhalation of pyrethroid insecticides.
* Doi H,
* Kikuchi H,
* Murai H,
* Kawano Y,
* Shigeto H,
* Ohyagi Y,
* Kira J.
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
PMID: 17130437 [PubMed - indexed for MEDLINE]
15: Nat Methods. 2006 Nov;3(11):876.
siRNAs meet their match.
Potash J.
A new study addresses how to design highly specific small interfering RNAs
(siRNAs) capable of distinguishing between similar variants of the same gene.
PMID: 17124734 [PubMed - indexed for MEDLINE]
siRNAs meet their match.
Potash J.
A new study addresses how to design highly specific small interfering RNAs
(siRNAs) capable of distinguishing between similar variants of the same gene.
PMID: 17124734 [PubMed - indexed for MEDLINE]
14: Neurol Sci. 2006 Nov;27(5):312-6.
Effect of nitric oxide on lymphocytes from sporadic amyotrophic lateral
sclerosis patients: toxic or protective role?
Cereda C, Cova E, Di Poto C, Galli A, Mazzini G, Corato M, Ceroni M.
Laboratory of Experimental Neurobiology, I.R.C.C.S. Foundation C. Mondino
Institute of Neurology, Centro Ricerche, Via Mondino 1, I-27100 Pavia, Italy.
cristina.cereda@mondino.it
Markers of oxidative and nitrosative stress have been found in spinal cord, cortex, cerebrospinal fluid and plasma of patients affected by amyotrophic lateral sclerosis (ALS), a fatal disorder characterised by progressive motor neuron degeneration. In this study, we investigated the effect of the NO-releasing agent, diethylamine NONOate (NONO), on lymphocytes from patients affected by the sporadic form of ALS (SALS) and controls by flow cytometry. In the same experimental conditions we investigated the expression of the antioxidant proteins, Bcl-2 and SOD1. Incubation with NONO induced cell damage in control lymphocytes but did not further damage the already affected untreated SALS lymphocytes. The incubation with NONO induced a time-dependent decrease of Bcl-2 and SOD1 in control lymphocytes. Surprisingly, in SALS lymphocytes the NONO treatment increased the expression of these proteins, which in basal conditions was depressed compared to control lymphocytes.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 17122939 [PubMed - indexed for MEDLINE]
Effect of nitric oxide on lymphocytes from sporadic amyotrophic lateral
sclerosis patients: toxic or protective role?
Cereda C, Cova E, Di Poto C, Galli A, Mazzini G, Corato M, Ceroni M.
Laboratory of Experimental Neurobiology, I.R.C.C.S. Foundation C. Mondino
Institute of Neurology, Centro Ricerche, Via Mondino 1, I-27100 Pavia, Italy.
cristina.cereda@mondino.it
Markers of oxidative and nitrosative stress have been found in spinal cord, cortex, cerebrospinal fluid and plasma of patients affected by amyotrophic lateral sclerosis (ALS), a fatal disorder characterised by progressive motor neuron degeneration. In this study, we investigated the effect of the NO-releasing agent, diethylamine NONOate (NONO), on lymphocytes from patients affected by the sporadic form of ALS (SALS) and controls by flow cytometry. In the same experimental conditions we investigated the expression of the antioxidant proteins, Bcl-2 and SOD1. Incubation with NONO induced cell damage in control lymphocytes but did not further damage the already affected untreated SALS lymphocytes. The incubation with NONO induced a time-dependent decrease of Bcl-2 and SOD1 in control lymphocytes. Surprisingly, in SALS lymphocytes the NONO treatment increased the expression of these proteins, which in basal conditions was depressed compared to control lymphocytes.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 17122939 [PubMed - indexed for MEDLINE]
13: Neurology. 2006 Nov 14;67(9):1652-8.
Longitudinal predictors of psychological distress and self-esteem in people with
ALS.
Goldstein LH, Atkins L, Landau S, Brown RG, Leigh PN.
MRC Center for Neurodegeneration Research, King's College London, Department of Psychology, Institute of Psychiatry, UK. l.goldstein@iop.kcl.ac.uk
OBJECTIVE: To identify predictors of psychological distress (measured by anxiety and depression) and low self-esteem and to determine whether these change over time in people with ALS. METHOD: We interviewed 50 patients with ALS living with a spouse/partner; further interviews were held at median intervals of 6 and then 5 months. Although carers were interviewed, we report the patients' data. Patients completed measures about their social support and marital relationship;
the functional impact of ALS; everyday cognitive, emotional, and behavioral changes; symptoms of anxiety and depression; and self-esteem. The ALS Severity Scale was also completed. RESULTS: From the initial sample of 50, 26 patients were interviewed on all three occasions. At the first interview, negative social support and bulbar impairment were most predictive of psychological distress; pre-illness marital intimacy was the best predictor of patients' self-esteem. Over time, negative social support and pre-illness marital intimacy retained an ability to predict patients' affective state and self-esteem. CONCLUSIONS: Social factors are important in determining longer-term psychological well-being in people with ALS who are in the relatively early stages of the disease.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17101899 [PubMed - indexed for MEDLINE]
Longitudinal predictors of psychological distress and self-esteem in people with
ALS.
Goldstein LH, Atkins L, Landau S, Brown RG, Leigh PN.
MRC Center for Neurodegeneration Research, King's College London, Department of Psychology, Institute of Psychiatry, UK. l.goldstein@iop.kcl.ac.uk
OBJECTIVE: To identify predictors of psychological distress (measured by anxiety and depression) and low self-esteem and to determine whether these change over time in people with ALS. METHOD: We interviewed 50 patients with ALS living with a spouse/partner; further interviews were held at median intervals of 6 and then 5 months. Although carers were interviewed, we report the patients' data. Patients completed measures about their social support and marital relationship;
the functional impact of ALS; everyday cognitive, emotional, and behavioral changes; symptoms of anxiety and depression; and self-esteem. The ALS Severity Scale was also completed. RESULTS: From the initial sample of 50, 26 patients were interviewed on all three occasions. At the first interview, negative social support and bulbar impairment were most predictive of psychological distress; pre-illness marital intimacy was the best predictor of patients' self-esteem. Over time, negative social support and pre-illness marital intimacy retained an ability to predict patients' affective state and self-esteem. CONCLUSIONS: Social factors are important in determining longer-term psychological well-being in people with ALS who are in the relatively early stages of the disease.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17101899 [PubMed - indexed for MEDLINE]
12: J Neurosci. 2006 Nov 8;26(45):11798-806.
Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in
amyotrophic lateral sclerosis through altered AMPA receptor trafficking.
Lai C, Xie C, McCormack SG, Chiang HC, Michalak MK, Lin X, Chandran J, Shim H,
Shimoji M, Cookson MR, Huganir RL, Rothstein JD, Price DL, Wong PC, Martin LJ,
Zhu JJ, Cai H.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of
Health, Bethesda, Maryland 20892-3707, USA.
Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease is caused by a selective loss of motor neurons. One form of juvenile onset autosomal recessive ALS (ALS2) has been linked to the loss of function of the ALS2 gene. The pathogenic mechanism of ALS2-deficiency, however, remains unclear. To further understand the function of alsin that is encoded by the full-length ALS2 gene, we screened proteins interacting with alsin. Here, we report that alsin interacted with glutamate receptor interacting protein 1 (GRIP1) both in vitro and in vivo, and colocalized with GRIP1 in neurons. In support of the physiological interaction between alsin and GRIP1, the subcellular distribution of GRIP1 was altered in ALS2(-/-) spinal motor neurons, which correlates with a significant reduction of AMPA-type glutamate receptor subunit 2 (GluR2) at the synaptic/cell surface of ALS2(-/-) neurons. The decrease of calcium-impermeable GluR2-containing AMPA receptors at the cell/synaptic surface rendered ALS2(-/-) neurons more susceptible to glutamate receptor-mediated neurotoxicity. Our findings reveal a novel function of alsin in AMPA receptor trafficking and provide a novel pathogenic link between ALS2-deficiency and motor neuron degeneration, suggesting a protective role of
alsin in maintaining the survival of motor neurons.
Publication Types:
Comparative Study
In Vitro
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
PMID: 17093100 [PubMed - indexed for MEDLINE]
11: Ophthalmology. 2006 Nov;113(11):2111.e1-2.
Pigmentary retinopathy of ALS/PDC in Kii.
Kokubo Y, Ito K, Fukunaga T, Matsubara H, Kuzuhara S.
Publication Types:
Letter
PMID: 17074574 [PubMed - indexed for MEDLINE]
Pigmentary retinopathy of ALS/PDC in Kii.
Kokubo Y, Ito K, Fukunaga T, Matsubara H, Kuzuhara S.
Publication Types:
Letter
PMID: 17074574 [PubMed - indexed for MEDLINE]
10: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1150-7. Epub 2006 Sep 29.
The epidemiology of ALS and the role of population-based registries.
Beghi E, Logroscino G, Chio A, Hardiman O, Mitchell D, Swingler R, Traynor BJ;
on behalf of the EURALS Consortium.
Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano,
Italy. beghi@marionegri.it
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 17071060 [PubMed - indexed for MEDLINE]
The epidemiology of ALS and the role of population-based registries.
Beghi E, Logroscino G, Chio A, Hardiman O, Mitchell D, Swingler R, Traynor BJ;
on behalf of the EURALS Consortium.
Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano,
Italy. beghi@marionegri.it
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 17071060 [PubMed - indexed for MEDLINE]
9: Clin Chem. 2006 Nov;52(11):2107-14.
Markedly increased vitamin B12 concentrations attributable to IgG-IgM-vitamin
B12 immune complexes.
Bowen RA, Drake SK, Vanjani R, Huey ED, Grafman J, Horne MK 3rd.
Department of Laboratory Medicine, Warren Grant Magnuson Clinical Center,
National Institutes of Health, Bethesda, MD 20892-1508, USA.
BACKGROUND: High serum vitamin B12 concentrations have been reported in patients with hepatic disease, disseminated neoplasia, myeloproliferative disorders, and hypereosinophilic syndromes. We recently discovered an extraordinarily increased vitamin B12 concentration in a patient without these underlying conditions. METHODS: Affinity and size-exclusion chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and ELISA methods were used to determine the cause of the increased vitamin B12 concentrations in this patient's serum. RESULTS: The protein G column eluates from 2 apparently healthy volunteers and 2 patients with recent vitamin B12 treatment for anemia had vitamin B12 concentrations of <74 pmol/L, whereas the vitamin B12 concentration in the protein G column eluate from the patient was 7380 pmol/L. The elution profile from size-exclusion chromatography of vitamin B12-binding proteins in the patient's serum revealed an abnormal vitamin-B12-binding protein. SDS-PAGE analysis of the concentrated eluates from the protein G column, under reducing conditions, revealed an additional band with an apparent molecular mass of 76 kDa, which was not present in control column eluates. MALDI-TOF MS identified this band as an IgM heavy chain. By use of a modified ELISA, we determined that the IgM present in the patient's eluates was associated with the IgG to form IgG-IgM immune complexes. CONCLUSIONS: This case demonstrates the unusual circumstance of a patient with markedly increased vitamin B12 concentrations attributed to immune complexes composed of IgG, IgM, and vitamin B12 and illustrates techniques that can be used to identify this occurrence.
Publication Types:
Case Reports
PMID: 17068171 [PubMed - indexed for MEDLINE]
Markedly increased vitamin B12 concentrations attributable to IgG-IgM-vitamin
B12 immune complexes.
Bowen RA, Drake SK, Vanjani R, Huey ED, Grafman J, Horne MK 3rd.
Department of Laboratory Medicine, Warren Grant Magnuson Clinical Center,
National Institutes of Health, Bethesda, MD 20892-1508, USA.
BACKGROUND: High serum vitamin B12 concentrations have been reported in patients with hepatic disease, disseminated neoplasia, myeloproliferative disorders, and hypereosinophilic syndromes. We recently discovered an extraordinarily increased vitamin B12 concentration in a patient without these underlying conditions. METHODS: Affinity and size-exclusion chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and ELISA methods were used to determine the cause of the increased vitamin B12 concentrations in this patient's serum. RESULTS: The protein G column eluates from 2 apparently healthy volunteers and 2 patients with recent vitamin B12 treatment for anemia had vitamin B12 concentrations of <74 pmol/L, whereas the vitamin B12 concentration in the protein G column eluate from the patient was 7380 pmol/L. The elution profile from size-exclusion chromatography of vitamin B12-binding proteins in the patient's serum revealed an abnormal vitamin-B12-binding protein. SDS-PAGE analysis of the concentrated eluates from the protein G column, under reducing conditions, revealed an additional band with an apparent molecular mass of 76 kDa, which was not present in control column eluates. MALDI-TOF MS identified this band as an IgM heavy chain. By use of a modified ELISA, we determined that the IgM present in the patient's eluates was associated with the IgG to form IgG-IgM immune complexes. CONCLUSIONS: This case demonstrates the unusual circumstance of a patient with markedly increased vitamin B12 concentrations attributed to immune complexes composed of IgG, IgM, and vitamin B12 and illustrates techniques that can be used to identify this occurrence.
Publication Types:
Case Reports
PMID: 17068171 [PubMed - indexed for MEDLINE]
8: Nat Neurosci. 2006 Nov;9(11):1357.
Comment on:
Nat Neurosci. 2006 Nov;9(11):1371-81.
New clues for axonal repair in ALS.
Narasimhan K.
Publication Types:
Comment
News
PMID: 17066065 [PubMed - indexed for MEDLINE]
Comment on:
Nat Neurosci. 2006 Nov;9(11):1371-81.
New clues for axonal repair in ALS.
Narasimhan K.
Publication Types:
Comment
News
PMID: 17066065 [PubMed - indexed for MEDLINE]
7: J Clin Neurosci. 2006 Nov;13(9):908-12. Epub 2006 Oct 16.
Clinical utility of trapezius muscle studies in the evaluation of amyotrophic
lateral sclerosis.
Cho JY, Sung JJ, Min JH, Lee KW.
Department of Neurology, Ilsan Paik Hospital, Inje University College of
Medicine, Ilsan, Korea.
Needle electromyography (EMG) and determining the motor evoked potential (MEP) of the genioglossus (tongue) are difficult to perform in evaluation of the craniobulbar region in patients with amyotrophic lateral sclerosis (ALS). Needle EMG and MEP determination in the upper trapezius were carried out in 17 consecutive ALS patients. The needle EMG parameters recorded included abnormal spontaneous activity and motor unit action potential morphology. An upper motor neuron lesion was presumed when either response to cortical stimulation was absent, or the central conduction time was delayed (>mean + 2 SD). Of the 12 patients with limb-onset ALS, using needle EMG, 11 were found to have abnormalities in the upper trapezius, and only five in the tongue. Three of the six patients with isolated limb involvement had abnormal MEP findings. In conclusion, electrophysiological studies of the upper trapezius are useful in ALS patients without bulbar symptoms.
PMID: 17049243 [PubMed - indexed for MEDLINE]
6: Expert Opin Investig Drugs. 2006 Nov;15(11):1383-93.
Catalytic antioxidants to treat amyotropic lateral sclerosis.
Crow JP.
University of Arkansas for Medical Sciences, College of Medicine, 4301 W.
Markham Slot 638, Little Rock, AR 72205, USA. jpcrow@uams.edu
Catalytic antioxidants are comprised of specialised classes of organometallic complexes that can catalyse the decomposition of injurious biological oxidants. These complexes have been shown to prevent the formation of several oxidative markers in spinal cord of G93A amyotropic lateral sclerosis mice and markedly extend survival, even when administered at symptom onset; however, it is now clear that some complexes lacking in antioxidant activity are also protective. New proteomics data suggest that these complexes also induce a broad spectrum of endogenous cellular defense mechanisms. The combination of antioxidant and adaptive resistance effects may explain the remarkable potency of these compounds and may also suggest wide applicability for them in a number of neurodegenerative diseases.
Publication Types:
Review
PMID: 17040198 [PubMed - indexed for MEDLINE]
Catalytic antioxidants to treat amyotropic lateral sclerosis.
Crow JP.
University of Arkansas for Medical Sciences, College of Medicine, 4301 W.
Markham Slot 638, Little Rock, AR 72205, USA. jpcrow@uams.edu
Catalytic antioxidants are comprised of specialised classes of organometallic complexes that can catalyse the decomposition of injurious biological oxidants. These complexes have been shown to prevent the formation of several oxidative markers in spinal cord of G93A amyotropic lateral sclerosis mice and markedly extend survival, even when administered at symptom onset; however, it is now clear that some complexes lacking in antioxidant activity are also protective. New proteomics data suggest that these complexes also induce a broad spectrum of endogenous cellular defense mechanisms. The combination of antioxidant and adaptive resistance effects may explain the remarkable potency of these compounds and may also suggest wide applicability for them in a number of neurodegenerative diseases.
Publication Types:
Review
PMID: 17040198 [PubMed - indexed for MEDLINE]
5: Neurology. 2006 Nov 14;67(9):1659-64.
The ALSSQOL: balancing physical and nonphysical factors in assessing quality of
life in ALS.
Simmons Z, Felgoise SH, Bremer BA, Walsh SM, Hufford DJ, Bromberg MB, David W,
Forshew DA, Heiman-Patterson TD, Lai EC, McCluskey L.
Department of Neurology, Penn State College of Medicine, Hershey, PA 17033, USA.
zsimmons@psu.edu
BACKGROUND: There is no generally accepted instrument for measuring quality of life (QOL) in patients with ALS. Current instruments are either too heavily weighted toward strength and physical function or useful for the evaluation of individuals but of less utility in assessing large samples. OBJECTIVE: To develop and evaluate the psychometric properties of an ALS-specific QOL instrument (the ALSSQOL) that would reflect overall QOL as assessed by the patient and would be valid and reliable across large samples. METHODS: The ALSSQOL is based on the McGill Quality of Life Questionnaire (MQOL), modified by changes in format and by adding questions on religiousness and spirituality, items derived from interviews with ALS patients, and items identified from open-ended questions administered during the MQOL. The psychometric properties of the ALSSQOL were assessed by a prospective multicenter study in which participants completed the ALSSQOL, other instruments measuring overall QOL, and instruments assessing religiousness, spirituality, and psychological distress. RESULTS: A 59-item ALSSQOL was developed; 342 patients evaluated its psychometric properties. Completion time averaged 15 minutes. Forty-six items loaded on six factors. The ALSSQOL demonstrated concurrent, convergent, and discriminant validity for the overall instrument and convergent validity for its subscales. Analysis of individual items permitted insight into variables of clinical importance. CONCLUSIONS: This new ALS-specific quality of life instrument is a practical tool for the assessment of overall quality of life in individuals with ALS and appears to be valid and useful across large samples.
Validation studies of a shortened version are now under way.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17101900 [PubMed - indexed for MEDLINE]
The ALSSQOL: balancing physical and nonphysical factors in assessing quality of
life in ALS.
Simmons Z, Felgoise SH, Bremer BA, Walsh SM, Hufford DJ, Bromberg MB, David W,
Forshew DA, Heiman-Patterson TD, Lai EC, McCluskey L.
Department of Neurology, Penn State College of Medicine, Hershey, PA 17033, USA.
zsimmons@psu.edu
BACKGROUND: There is no generally accepted instrument for measuring quality of life (QOL) in patients with ALS. Current instruments are either too heavily weighted toward strength and physical function or useful for the evaluation of individuals but of less utility in assessing large samples. OBJECTIVE: To develop and evaluate the psychometric properties of an ALS-specific QOL instrument (the ALSSQOL) that would reflect overall QOL as assessed by the patient and would be valid and reliable across large samples. METHODS: The ALSSQOL is based on the McGill Quality of Life Questionnaire (MQOL), modified by changes in format and by adding questions on religiousness and spirituality, items derived from interviews with ALS patients, and items identified from open-ended questions administered during the MQOL. The psychometric properties of the ALSSQOL were assessed by a prospective multicenter study in which participants completed the ALSSQOL, other instruments measuring overall QOL, and instruments assessing religiousness, spirituality, and psychological distress. RESULTS: A 59-item ALSSQOL was developed; 342 patients evaluated its psychometric properties. Completion time averaged 15 minutes. Forty-six items loaded on six factors. The ALSSQOL demonstrated concurrent, convergent, and discriminant validity for the overall instrument and convergent validity for its subscales. Analysis of individual items permitted insight into variables of clinical importance. CONCLUSIONS: This new ALS-specific quality of life instrument is a practical tool for the assessment of overall quality of life in individuals with ALS and appears to be valid and useful across large samples.
Validation studies of a shortened version are now under way.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17101900 [PubMed - indexed for MEDLINE]
4: Clin Neurophysiol. 2006 Nov;117(11):2451-8. Epub 2006 Sep 25.
Increased nodal persistent Na+ currents in human neuropathy and motor neuron
disease estimated by latent addition.
Tamura N, Kuwabara S, Misawa S, Kanai K, Nakata M, Sawai S, Hattori T.
Department of Neurology, Chiba University School of Medicine, 1-8-1 Inohana,
Chuo-ku, Chiba 260-8670, Japan.
OBJECTIVE: To investigate the changes in nodal persistent Na(+) currents in human neuropathy and motor neuron disease. In human motor axons, approximately 1.0% of total Na(+) channels are active at rest, termed "persistent" Na(+) channels, and the conductance can be non-invasively estimated by the technique of latent addition in vivo. METHODS: Latent addition was performed in median motor axons of 93 patients with axonal neuropathy (n=38), lower motor neuron disorder (LMND; n=19) or amyotrophic lateral sclerosis (ALS; n=36) and in 27 age-matched normal subjects. Brief hyperpolarizing conditioning current pulses were delivered, and threshold change at the conditioning-test interval of 0.2 ms was measured as an estimator of the magnitude of persistent Na(+) currents. Threshold electrotonus and supernormality were also measured as indicators of resting membrane potential. RESULTS: Threshold changes at 0.2 ms were significantly greater in patients with neuropathy or LMND (p<0.05), and tended to be greater in ALS patients (p=0.075) than in normal controls. Threshold
electrotonus and supernormality did not differ in each patient group and normal
controls, suggesting that membrane potential is not altered in patients. In the
recovery phase of axonal neuropathy, the threshold changes increased in parallel
with an increase in amplitudes of compound muscle action potential. CONCLUSIONS:
Persistent Na(+) currents appear to increase commonly in disorders involving lower motor neurons, possibly associated with axonal regeneration or collateral sprouting or changes in Na(+) channel gating. SIGNIFICANCE: The increased axonal excitability could partly be responsible for positive motor symptoms such as muscle cramping frequently seen in lower motor neuron disorders.
PMID: 16996798 [PubMed - indexed for MEDLINE]
Increased nodal persistent Na+ currents in human neuropathy and motor neuron
disease estimated by latent addition.
Tamura N, Kuwabara S, Misawa S, Kanai K, Nakata M, Sawai S, Hattori T.
Department of Neurology, Chiba University School of Medicine, 1-8-1 Inohana,
Chuo-ku, Chiba 260-8670, Japan.
OBJECTIVE: To investigate the changes in nodal persistent Na(+) currents in human neuropathy and motor neuron disease. In human motor axons, approximately 1.0% of total Na(+) channels are active at rest, termed "persistent" Na(+) channels, and the conductance can be non-invasively estimated by the technique of latent addition in vivo. METHODS: Latent addition was performed in median motor axons of 93 patients with axonal neuropathy (n=38), lower motor neuron disorder (LMND; n=19) or amyotrophic lateral sclerosis (ALS; n=36) and in 27 age-matched normal subjects. Brief hyperpolarizing conditioning current pulses were delivered, and threshold change at the conditioning-test interval of 0.2 ms was measured as an estimator of the magnitude of persistent Na(+) currents. Threshold electrotonus and supernormality were also measured as indicators of resting membrane potential. RESULTS: Threshold changes at 0.2 ms were significantly greater in patients with neuropathy or LMND (p<0.05), and tended to be greater in ALS patients (p=0.075) than in normal controls. Threshold
electrotonus and supernormality did not differ in each patient group and normal
controls, suggesting that membrane potential is not altered in patients. In the
recovery phase of axonal neuropathy, the threshold changes increased in parallel
with an increase in amplitudes of compound muscle action potential. CONCLUSIONS:
Persistent Na(+) currents appear to increase commonly in disorders involving lower motor neurons, possibly associated with axonal regeneration or collateral sprouting or changes in Na(+) channel gating. SIGNIFICANCE: The increased axonal excitability could partly be responsible for positive motor symptoms such as muscle cramping frequently seen in lower motor neuron disorders.
PMID: 16996798 [PubMed - indexed for MEDLINE]
3: Neuromuscul Disord. 2006 Nov;16(11):800-4. Epub 2006 Sep 6.
SOD1 gene mutations in Italian patients with Sporadic Amyotrophic Lateral
Sclerosis (ALS).
Corrado L, D'Alfonso S, Bergamaschi L, Testa L, Leone M, Nasuelli N,
Momigliano-Richiardi P, Mazzini L.
Department of Medical Sciences, University of Eastern Piedmont, Novara, Italy.
lucia.corrado@med.unipmn.it
Mutations in the SOD1 gene exons and exon/intron boundaries were searched in 66 sporadic and 4 familial Italian ALS cases consecutively referred to our centre from different Italian regions. A mutation was found in three sporadic cases (4.5%): a new nonsense mutation in exon 5 (K136X) in a patient with a rapid and severe disease course and two previously described missense nucleotide substitutions (N65S and A95T) in two patients with a mild disease course. Comparison of the clinical characteristics with previously reported patients carrying the same or similar mutations showed a remarkable genotype-phenotype correlation. No association was found with intronic sequence variations by comparing their frequency in the patients and in 181 matched controls.
PMID: 16952453 [PubMed - indexed for MEDLINE]
SOD1 gene mutations in Italian patients with Sporadic Amyotrophic Lateral
Sclerosis (ALS).
Corrado L, D'Alfonso S, Bergamaschi L, Testa L, Leone M, Nasuelli N,
Momigliano-Richiardi P, Mazzini L.
Department of Medical Sciences, University of Eastern Piedmont, Novara, Italy.
lucia.corrado@med.unipmn.it
Mutations in the SOD1 gene exons and exon/intron boundaries were searched in 66 sporadic and 4 familial Italian ALS cases consecutively referred to our centre from different Italian regions. A mutation was found in three sporadic cases (4.5%): a new nonsense mutation in exon 5 (K136X) in a patient with a rapid and severe disease course and two previously described missense nucleotide substitutions (N65S and A95T) in two patients with a mild disease course. Comparison of the clinical characteristics with previously reported patients carrying the same or similar mutations showed a remarkable genotype-phenotype correlation. No association was found with intronic sequence variations by comparing their frequency in the patients and in 181 matched controls.
PMID: 16952453 [PubMed - indexed for MEDLINE]
2: J Biol Chem. 2006 Nov 3;281(44):33325-35. Epub 2006 Aug 30.
Insoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral
sclerosis mice.
Basso M, Massignan T, Samengo G, Cheroni C, De Biasi S, Salmona M, Bendotti C,
Bonetto V.
Dulbecco Telethon Institute, Milan, Italy.
Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause a familial form of
amyotrophic lateral sclerosis (ALS) through an unknown gain-of-function
mechanism. Mutant SOD1 aggregation may be the toxic property. In fact,
proteinaceous inclusions rich in mutant SOD1 have been found in tissues from the
familial form of ALS patients and in mutant SOD1 animals, before disease onset.
However, very little is known of the constituents and mechanism of formation of
aggregates in ALS. We and others have shown that there is a progressive
accumulation of detergent-insoluble mutant SOD1 in the spinal cord of G93A SOD1
mice. To investigate the mechanism of SOD1 aggregation, we characterized by
proteome technologies SOD1 isoforms in a Triton X-100-insoluble fraction of
spinal cord from G93A SOD1 mice at different stages of the disease. This showed
that at symptomatic stages of the disease, part of the insoluble SOD1 is
unambiguously mono- and oligoubiquitinated, in spinal cord and not in
hippocampus, and that ubiquitin branches at Lys(48), the major signal for
proteasome degradation. At presymptomatic stages of the disease, only insoluble
unmodified SOD1 is recovered. Partial ubiquitination of SOD1-rich inclusions was
also confirmed by immunohistochemical and electron microscopy analysis of lumbar
spinal cord sections from symptomatic G93A SOD1 mice. On the basis of these
results, we propose that ubiquitination occurs only after SOD1 aggregation and
that oligoubiquitination may underline alternative mechanisms in disease
pathogenesis.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16943203 [PubMed - indexed for MEDLINE]
Insoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral
sclerosis mice.
Basso M, Massignan T, Samengo G, Cheroni C, De Biasi S, Salmona M, Bendotti C,
Bonetto V.
Dulbecco Telethon Institute, Milan, Italy.
Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause a familial form of
amyotrophic lateral sclerosis (ALS) through an unknown gain-of-function
mechanism. Mutant SOD1 aggregation may be the toxic property. In fact,
proteinaceous inclusions rich in mutant SOD1 have been found in tissues from the
familial form of ALS patients and in mutant SOD1 animals, before disease onset.
However, very little is known of the constituents and mechanism of formation of
aggregates in ALS. We and others have shown that there is a progressive
accumulation of detergent-insoluble mutant SOD1 in the spinal cord of G93A SOD1
mice. To investigate the mechanism of SOD1 aggregation, we characterized by
proteome technologies SOD1 isoforms in a Triton X-100-insoluble fraction of
spinal cord from G93A SOD1 mice at different stages of the disease. This showed
that at symptomatic stages of the disease, part of the insoluble SOD1 is
unambiguously mono- and oligoubiquitinated, in spinal cord and not in
hippocampus, and that ubiquitin branches at Lys(48), the major signal for
proteasome degradation. At presymptomatic stages of the disease, only insoluble
unmodified SOD1 is recovered. Partial ubiquitination of SOD1-rich inclusions was
also confirmed by immunohistochemical and electron microscopy analysis of lumbar
spinal cord sections from symptomatic G93A SOD1 mice. On the basis of these
results, we propose that ubiquitination occurs only after SOD1 aggregation and
that oligoubiquitination may underline alternative mechanisms in disease
pathogenesis.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16943203 [PubMed - indexed for MEDLINE]
1: J Neurochem. 2006 Nov;99(3):900-12. Epub 2006 Aug 21.
Progressive loss of a glial potassium channel (KCNJ10) in the spinal cord of the
SOD1 (G93A) transgenic mouse model of amyotrophic lateral sclerosis.
Kaiser M, Maletzki I, Hulsmann S, Holtmann B, Schulz-Schaeffer W, Kirchhoff F,
Bahr M, Neusch C.
Department of Neurology, Georg-August University Gottingen, Gottingen, Germany.
Transgenic mice expressing the superoxide dismutase G93A mutation (SOD1(G93A))
were used to investigate the role of glial inwardly rectifying K(+) (Kir)4.1 channels, which buffer extracellular K(+) increases in response to neuronal excitation. A progressive decrease in Kir4.1 immunoreactivity was observed predominantly in the ventral horn of SOD1(G93A) mutants. Immunoblotting of spinal cord extracts mirrored these changes by showing a loss of Kir4.1 channels from presymptomatic stages onwards. Kir4.1 channels were found to be expressed in the spinal cord grey matter, targetting astrocytes and clustering around capillaries, supporting their role in clearance of extracellular K(+). To
understand the functional implications of extracellular K(+) increases, we challenged the NSC34 motor neurone cell line with increasing extracellular K(+) concentrations. Exposure to high extracellular K(+) induced progressive motor neurone cell death. We suggest that loss of Kir4.1 impairs perineural K(+) homeostasis and may contribute to motor neurone degeneration in SOD1(G93A) mutants by K(+) excitotoxic mechanisms.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16925593 [PubMed - indexed for MEDLINE]
Progressive loss of a glial potassium channel (KCNJ10) in the spinal cord of the
SOD1 (G93A) transgenic mouse model of amyotrophic lateral sclerosis.
Kaiser M, Maletzki I, Hulsmann S, Holtmann B, Schulz-Schaeffer W, Kirchhoff F,
Bahr M, Neusch C.
Department of Neurology, Georg-August University Gottingen, Gottingen, Germany.
Transgenic mice expressing the superoxide dismutase G93A mutation (SOD1(G93A))
were used to investigate the role of glial inwardly rectifying K(+) (Kir)4.1 channels, which buffer extracellular K(+) increases in response to neuronal excitation. A progressive decrease in Kir4.1 immunoreactivity was observed predominantly in the ventral horn of SOD1(G93A) mutants. Immunoblotting of spinal cord extracts mirrored these changes by showing a loss of Kir4.1 channels from presymptomatic stages onwards. Kir4.1 channels were found to be expressed in the spinal cord grey matter, targetting astrocytes and clustering around capillaries, supporting their role in clearance of extracellular K(+). To
understand the functional implications of extracellular K(+) increases, we challenged the NSC34 motor neurone cell line with increasing extracellular K(+) concentrations. Exposure to high extracellular K(+) induced progressive motor neurone cell death. We suggest that loss of Kir4.1 impairs perineural K(+) homeostasis and may contribute to motor neurone degeneration in SOD1(G93A) mutants by K(+) excitotoxic mechanisms.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16925593 [PubMed - indexed for MEDLINE]
