44: S Afr Med J. 2006 Dec;96(12):1216.
PMID: 17252143 [PubMed - indexed for MEDLINE]
43: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):956-72. Epub 2006 Feb 10.
Genetics of familial and sporadic amyotrophic lateral sclerosis.
Gros-Louis F, Gaspar C, Rouleau GA.
Center for the Study of Brain Diseases, CHUM Research Center, Notre Dame Hospital, J.A. de Seve Pavillion, Room Y-3633, 1560, Sherbrooke Street East, Montreal, QC, Canada H2L 4M1.
Diseases affecting motor neurons, such as amyotrophic lateral sclerosis (Lou Gerhig's disease), hereditary spastic paraplegia and spinal bulbar muscular atrophy (Kennedy's disease) are a heterogeneous group of chronic progressive diseases and are among the most puzzling yet untreatable illnesses. Over the last decade, identification of mutations in genes predisposing to these disorders has provided the means to better understand their pathogenesis. The discovery 13 years ago of SOD1 mutations linked to ALS, which account for less than 2% of total cases, had a major impact in the field. However, despite
intensive research effort, the pathways leading to the specific motor neurons degeneration in the presence of SOD1 mutations have not been fully identified. This review provides an overview of the genetics of both familial and sporadic forms of ALS.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16503123 [PubMed - indexed for MEDLINE]
42: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1083-93. Epub 2006 Mar 31.
Innate immunity in amyotrophic lateral sclerosis.
Moisse K, Strong MJ.
Cell Biology Research Group, Robarts Research Institute, Department of Clinical
Neurological Sciences, The University of Western Ontario, London, Ontario,
Canada.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motor neurons are selectively targeted. Although the underlying cause remains unclear, evidence suggests a role for innate immunity in disease pathogenesis. Neuroinflammation in areas of motor neuron loss is evident in presymptomatic mouse models of ALS and in human patients. Efforts aimed at attenuating the inflammatory response in ALS animal models have delayed symptom onset and extended survival. Seemingly conversely, attempts to sensitize cells of the innate immune system and modulate their phenotype have also shown efficacy. Effectors of innate immunity in the CNS appear to have ambivalent potential to promote either repair or injury. Because ALS is a syndromic disease in which glutamate excitotoxicity, altered cytoskeletal protein metabolism, oxidative injury, mitochondrial dysfunction and neuroinflammation all contribute to motor neuron degeneration, targeting inflammation via modulation of
microglial function therefore holds significant potential as one aspect of therapeutic intervention and could provide insight into the exclusive vulnerability of motor neurons.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16624536 [PubMed - indexed for MEDLINE]
41: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1013-24. Epub 2006 Apr 21.
Transgenic mouse models of amyotrophic lateral sclerosis.
Julien JP, Kriz J.
Research Centre of CHUL, Department of Anatomy and Physiology of Laval
University, 2705 Boulevard Laurier, Quebec, QC, Canada G1V 4G2.
jean-pierre.julien@crchul.ulaval.ca
The discovery of missense mutations in the gene coding for the Cu/Zn superoxide
dismutase 1 (SOD1) in subsets of familial cases was rapidly followed by the generation of transgenic mice expressing various forms of SOD1 mutants. The mice overexpressing high levels of mutant SOD1 mRNAs do develop motor neuron disease but unraveling the mechanisms of pathogenesis has been very challenging. Studies with mouse lines suggest that the toxicity of mutant SOD1 is unrelated to copper-mediated catalysis but rather to propensity of a subfraction of mutant SOD1 proteins to form misfolded protein species and aggregates. However, the mechanism of toxicity of SOD1 mutants remains to be elucidated. Involvement of cytoskeletal components in ALS pathogenesis is supported by several mouse models of motor neuron disease with neurofilament abnormalities and with genetic defects in microtubule-based transport. Here, we describe how transgenic mouse models have been used for understanding pathogenic pathways of motor neuron
disease and for pre-clinical drug testing.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16675207 [PubMed - indexed for MEDLINE]
40: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1051-67. Epub 2006 Apr 4.
Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target.
Barber SC, Mead RJ, Shaw PJ.
Academic Neurology Unit, Section of Neuroscience, E Floor, Medical School, Beech
Hill Road, Sheffield S10 2RX, UK.
The cause(s) of amyotrophic lateral sclerosis (ALS) is not fully understood in the vast majority of cases and the mechanisms involved in motor neuron degeneration are multi-factorial and complex. There is substantial evidence to support the hypothesis that oxidative stress is one mechanism by which motor neuron death occurs. This theory becomes more persuasive with the discovery that mutation of the anti-oxidant enzyme, superoxide dismutase 1 (SOD1), causes disease in a significant minority of cases. However, the precise mechanism(s) by which mutant SOD1 leads to motor neuron degeneration have not been defined with certainty, and trials of anti-oxidant therapies have been disappointing. Here, we review the evidence implicating oxidative stress in ALS pathogenesis, discuss how oxidative stress may affect and be affected by other proposed mechanisms of neurodegeneration, and review the trials of various anti-oxidants as potential therapies for ALS.
Publication Types:
Review
PMID: 16713195 [PubMed - indexed for MEDLINE]
39: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1139-49. Epub 2006 Apr 4.
Translating preclinical insights into effective human trials in ALS.
DiBernardo AB, Cudkowicz ME.
Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA.
adibernardo@partners.org
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, adult-onset neurodegenerative disease characterized by selective dysfunction and death of motor neurons in the brain and spinal cord. The disease is typically fatal within 3-5 years of symptom onset. There is no known cure and only riluzole, which was approved by the FDA in 1996 for treatment of ALS, has shown some efficacy in humans. Preclinical insights from model systems continue to furnish ample therapeutic targets, however, translation into effective therapies for humans remains challenging. We present an overview of clinical trial methodology for ALS, including a summary rationale for target selection and challenges to ALS clinical research.
Publication Types:
Review
PMID: 16713196 [PubMed - indexed for MEDLINE]
38: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1094-108. Epub 2006 Apr 19.
Axonal transport and neurodegenerative disease.
Chevalier-Larsen E, Holzbaur EL.
University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6046, USA.
Neurons have extensive processes and communication between those processes and
the cell body is crucial to neuronal function and survival. Thus, neurons are uniquely dependent on microtubule based transport. Growing evidence supports the idea that deficits in axonal transport contribute to pathogenesis in multiple neurodegenerative diseases. We describe the motor, cytoskeletal, and adaptor proteins involved in axonal transport and their interactions. Data linking disruption of axonal transport to diseases such as ALS are discussed. Finally, we explore the pathways that may cause neuronal dysfunction and death.
Publication Types:
Review
PMID: 16730956 [PubMed - indexed for MEDLINE]
37: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):986-1000. Epub 2006 May 5.
The molecular genetics of non-ALS motor neuron diseases.
James PA, Talbot K.
Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, UK.
Hereditary disorders of voluntary motor neurons are individually relatively uncommon, but have the potential to provide significant insights into motor neuron function in general and into the mechanisms underlying the more common form of sporadic Amyotrophic Lateral Sclerosis. Recently, mutations in a number of novel genes have been associated with Lower Motor Neuron (HSPB1, HSPB8, GARS, Dynactin), Upper Motor Neuron (Spastin, Atlastin, Paraplegin, HSP60, KIF5A, NIPA1) or mixed ALS-like phenotypes (Alsin, Senataxin, VAPB, BSCL2). In comparison to sporadic ALS these conditions are usually associated with slow progression, but as experience increases, a wide variation in clinical phenotype has become apparent. At the molecular level common themes are emerging that point to areas of specific vulnerability for motor neurons such as axonal transport, endosomal trafficking and RNA processing. We review the clinical and molecular features of this diverse group of genetically determined conditions and consider the implications for the broad group of motor neuron diseases in general.
Publication Types:
Review
PMID: 16765570 [PubMed - indexed for MEDLINE]
36: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1109-21. Epub 2006 May 9.
VEGF at the neurovascular interface: therapeutic implications for motor neuron disease.
Lambrechts D, Carmeliet P.
Center for Transgene Technology and Gene Therapy, Flanders Interuniversitary Institute for Biotechnology, KULeuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
VEGF was discovered almost 25 years ago, and its angiogenic activity has been
extensively studied ever since. Accumulating evidence indicates, however, that VEGF also has direct effects on neuronal cells. VEGF exerts neuroprotective effects on various cultured neurons of the central nervous system. In vivo, VEGF controls the correct migration of facial branchiomotor neurons in the developing hindbrain and stimulates the proliferation of neural stem cells in enriched environments and after cerebral ischemia. Transgenic mice expressing reduced levels of VEGF develop late-onset motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis (ALS), whereas reduced levels of VEGF have been implicated in a polyglutamine-induced model of motor neuron degeneration. Recent data further reveal that intracerebroventricular delivery of recombinant VEGF protein delays disease onset and prolongs survival of ALS rats, whereas intramuscular administration of a VEGF-expressing lentiviral vector increases
the life expectancy of ALS mice by as much as 30%. Deciphering the precise role
of VEGF at the neurovascular interface promises to uncover new insights into the development and pathology of the nervous system, helpful to design novel strategies to treat (motor) neurodegenerative disorders.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16784838 [PubMed - indexed for MEDLINE]
35: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1122-7. Epub 2006 May 22.
Gene Therapy for ALS: progress and prospects.
Azzouz M.
Academic Unit of Neurology, Medical School, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK. m.azzouz@sheffield.ac.uk
Amyotrophic lateral sclerosis (ALS) is a devastating disease for which there are no effective drug treatments to date. Recent advances in Gene Therapy open up the possibility of developing an effective treatment aiming at halting or delaying the degeneration of motor neurons. Viral vectors such as lentiviral vectors and adeno-associated virus can transfer genes into many different types of primary neurons from a broad range of species including man and the resulting gene expression is long-term. Numerous animal studies have now been undertaken with these vectors and correction of disease models has been obtained. These vectors have been refined to a very high level and can be produced safely for the clinic. However, we believe that there are some major issues that need to be addressed in order to see a Gene Therapy approach with viral vectors proceed to the clinic for ALS patients. This review will describe the general features of lentiviral vectors. It will then describe some key examples of gene transfer and
genetic correction in animal models of motor neuron disease. The prospects for the clinical evaluation of lentiviral vectors for the treatment of human motor neuron disease will be outlined.
Publication Types:
Review
PMID: 16806843 [PubMed - indexed for MEDLINE]
34: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1068-82. Epub 2006 May 17.
The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis.
Van Den Bosch L, Van Damme P, Bogaert E, Robberecht W.
Neurobiology, Campus Gasthuisberg O&N2, PB1022, Herestraat 49, B-3000 Leuven,
Belgium. Ludo.Vandenbosch@med.kuleuven.be
Unfortunately and despite all efforts, amyotrophic lateral sclerosis (ALS) remains an incurable neurodegenerative disorder characterized by the progressive and selective death of motor neurons. The cause of this process is mostly unknown, but evidence is available that excitotoxicity plays an important role. In this review, we will give an overview of the arguments in favor of the involvement of excitotoxicity in ALS. The most important one is that the only drug proven to slow the disease process in humans, riluzole, has
anti-excitotoxic properties. Moreover, consumption of excitotoxins can give rise to selective motor neuron death, indicating that motor neurons are extremely sensitive to excessive stimulation of glutamate receptors. We will summarize the intrinsic properties of motor neurons that could render these cells particularly sensitive to excitotoxicity. Most of these characteristics relate to the way motor neurons handle Ca(2+), as they combine two exceptional characteristics: a low Ca(2+)-buffering capacity and a high number of Ca(2+)-permeable AMPA receptors. These properties most likely are essential to perform their normal function, but under pathological conditions they could become responsible for the selective death of motor neurons. In order to achieve this worst-case scenario, additional factors/mechanisms could be required. In 1 to 2% of the ALS patients, mutations in the SOD1 gene could shift the balance from normal motor neuron excitation to excitotoxicity by decreasing glutamate uptake in the surrounding astrocytes and/or by interfering with mitochondrial function. We will discuss point by point these different pathogenic mechanisms that could give rise to classical and/or slow excitotoxicity leading to selective motor neuron death.
Publication Types:
Review
PMID: 16806844 [PubMed - indexed for MEDLINE]
33: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1025-37. Epub 2006 May 22.
Structure, folding, and misfolding of Cu,Zn superoxide dismutase in amyotrophic lateral sclerosis.
Rakhit R, Chakrabartty A.
Department of Biochemistry, University of Toronto, University Health Network, Toronto Medical Discovery Tower, Medical and Related Sciences (MaRS), 101 College Street, Toronto, ON, Canada, M5G 1L7.
Fourteen years after the discovery that mutations in Cu, Zn superoxide dismutase (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS), the mechanism by which mutant SOD1 exerts toxicity remains unknown. The two principle hypotheses are (a) oxidative damage stemming from aberrant SOD1 redox chemistry, and (b) misfolding of the mutant protein. Here we review the structure and function of wild-type SOD1, as well as the changes to the structure and function in mutant SOD1. The relative merits of the two hypotheses are compared and a common unifying principle is outlined. Lastly, the potential for therapies targeting SOD1 misfolding is discussed.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16814528 [PubMed - indexed for MEDLINE]
32: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1128-38. Epub 2006 Jun 17.
Cellular therapies in motor neuron diseases.
Nayak MS, Kim YS, Goldman M, Keirstead HS, Kerr DA.
Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are prototypical motor neuron diseases that result in progressive weakness as a result of motor neuron dysfunction and death. Though much work has been done in both diseases to identify the cellular mechanisms of motor neuron dysfunction, once motor neurons have died, one of potential therapies to restore function would be through the use of cellular transplantation. In this review, we discuss potential strategies whereby cellular therapies, including the use of stem cells, neural progenitors and cells engineered to secrete trophic factors, may be used in motor neuron diseases. We review pre-clinical data in rodents with each of these approaches and discuss advances and regulatory issues regarding the use of cellular therapies in human motor neuron diseases.
Publication Types:
Review
PMID: 16872810 [PubMed - indexed for MEDLINE]
31: Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1038-50. Epub 2006 Jun 18.
Failure of protein quality control in amyotrophic lateral sclerosis.
Kabashi E, Durham HD.
Department of Neurology/Neurosurgery and Montreal Neurological Institute, McGill
University, 3801 University St., Montreal QC, Canada H3A 2B4.
The protein chaperoning and ubiquitin-proteasome systems perform many homeostatic functions within cells involving protein folding, transport and degradation. Of paramount importance is ridding cells of mutant or post-translationally modified proteins that otherwise tend to aggregate into insoluble complexes and form inclusions. Such inclusions are characteristic of many neurodegenerative diseases and implicate protein misfolding and aggregation as common aspects of pathogenesis. In the most common familial form of ALS, mutations in SOD1 promote misfolding of the protein and target it for
degradation by proteasomes. Although proteasomes can degrade the mutant proteins
efficiently, altered solubility and aggregation of mutant SOD1 are features of the disease and occur most prominently in the most vulnerable cells and tissues. Indeed, lumbar spinal cord of mutant SOD1 transgenic mice show early reduction in their capacity for protein chaperoning and proteasome-mediated hydrolysis of substrates, and motor neurons are particularly vulnerable to aggregation of mutant SOD1. A high threshold for upregulating key pathways in response to the stress of added substrate load may contribute to this vulnerability. The broad spectrum neuroprotective capability and efficacy of some chaperone-based therapies in preclinical models makes these pathways attractive as targets for therapy in ALS, as well as other neurodegenerative diseases. A better understanding of the mechanisms governing the regulation of protein chaperones
and UPS components would facilitate development of treatments that upregulate these pathways in a coordinated manner in neural tissue without long term toxicity.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16876390 [PubMed - indexed for MEDLINE]
30: Neurology. 2006 Dec 26;67(12):2260.
ALS in a patient with hereditary neuropathy with liability to pressure palsy.
Neurology/Neurophysiology Department, Cork University Hospital, Wilton, Cork, Ireland. sosulliv@ion.ucl.ac.uk
PMID: 17190961 [PubMed - indexed for MEDLINE]
29: Verh K Acad Geneeskd Belg. 2006 Dec ;68(4):249-69.
The causes and mechanism of selective motor neuron death in amyotrophic lateral sclerosis.
Labo Neurobiologie, KULeuven Campus Gasthuisberg O&N 2, Herestraat 49-B 3000, Leuven.
Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the selective death of motor neurons in the motor cortex, brain stem and spinal cord. In most cases, the cause of ALS is unknown although in a number of familial ALS cases mutations in the superoxide dismutase 1 (SOD1) gene were discovered. The mechanism underlying the selective motor neuron death is not yet clarified. However, it is clear that excitotoxicity could play a role in the selectivity of the motor neuron death. Excitotoxicity is the phenomenon in which the normal glutamate-mediated communication between neurons is disturbed and ultimately leads to neuronal death. In the first part of this study, we have investigated the intrinsic characteristics of motor neurons that could be responsible for the fact that these cells are extremely sensitive to excitotoxicity. Despite the fact that only the motor neurons die during ALS, it is clear that also other cell types play an important role during this process. In the second part of this study, we have concentrated on the potential role of the microglia. These cells are the macrophages of the brain and they become activated during inflammation. Using minocycline, we have inhibited the activation of the microglia and we have investigated its effect on the start of the disease and on the survival of a mouse model for ALS. Furthermore, we have investigated the cellular mechanism underlying the effect of minocycline. The goal of this research is to get insight into the mechanisms responsible for the selective motor neuron death during ALS and we hope that this information can help in the development of a therapy for this dramatic and incurable disease.
PMID: 17214440 [PubMed - indexed for MEDLINE]
28: Amyotroph Lateral Scler. 2006 Dec;7(4):235-40.
Manofluorographic evaluation of swallowing in amyotrophic lateral sclerosis and its relationship with clinical evaluation of swallowing.
Department of ENT Head and Neck Surgery, University Hospitals Leuven, Swallowing Clinic, Leuven, Belgium. Ann.Goeleven@uz.kuleuven.ac.be
The aim of this cross-sectional study was, first, to identify swallowing dysfunctions in an ALS population of 40 consecutive patients through combined videofluoroscopy and manometry. Secondly, these objective swallowing data were correlated with the functional feeding status as reported by the patient or family member. Videofluoroscopic evaluation showed dysfunctions in the oral phase of swallowing, pharyngeal initiation and pharyngeal transport. In addition, manometric data revealed low tongue driving forces and pharyngeal contraction amplitudes but normal relaxation of the upper oesophageal sphincter (UES). Aspiration was noted in a not negligible number of 9/40 patients. These objective data were then correlated with the clinical swallowing and feeding status, assessed by means of the ALS Swallowing Severity Scale. Patients receiving scores of 6 or lower on the ALSSSS, report dietary consistency changes but are considered 'safe oral feeders'. Nevertheless, our data revealed that these patients showed significant aspiration during videofluoroscopy. Although not every patient with ALS should be referred routinely for radiographic evaluation of swallowing, our findings suggest referral for a radiological examination as soon as the ALSSSS drops to a score of 6 or lower, to evaluate the presence of (silent) aspiration.
PMID: 17127562 [PubMed - indexed for MEDLINE]
