Showing papers on "Amyotrophic lateral sclerosis published in 2002"
TL;DR: Transgenic overexpression of Cu+2/Zn+2 superoxide dismutase 1 (SOD1) harboring an amyotrophic lateral sclerosis (ALS)-linked familial genetic mutation (S OD1G93A) in a Sprague–Dawley rat results in ALS-like motor neuron disease.
Abstract: Transgenic overexpression of Cu+2/Zn+2 superoxide dismutase 1 (SOD1) harboring an amyotrophic lateral sclerosis (ALS)-linked familial genetic mutation (SOD1G93A) in a Sprague–Dawley rat results in ALS-like motor neuron disease. Motor neuron disease in these rats depended on high levels of mutant SOD1 expression, increasing from 8-fold over endogenous SOD1 in the spinal cord of young presymptomatic rats to 16-fold in end-stage animals. Disease onset in these rats was early, ≈115 days, and disease progression was very rapid thereafter with affected rats reaching end stage on average within 11 days. Pathological abnormalities included vacuoles initially in the lumbar spinal cord and subsequently in more cervical areas, along with inclusion bodies that stained for SOD1, Hsp70, neurofilaments, and ubiquitin. Vacuolization and gliosis were evident before clinical onset of disease and before motor neuron death in the spinal cord and brainstem. Focal loss of the EAAT2 glutamate transporter in the ventral horn of the spinal cord coincided with gliosis, but appeared before motor neuron/axon degeneration. At end-stage disease, gliosis increased and EAAT2 loss in the ventral horn exceeded 90%, suggesting a role for this protein in the events leading to cell death in ALS. These transgenic rats provide a valuable resource to pursue experimentation and therapeutic development, currently difficult or impossible to perform with existing ALS transgenic mice.
852 citations
TL;DR: Immunohistochemical studies showed increased neuronal staining for hemeoxygenase‐1, malondialdehyde‐modified protein, and OH8dG in both SALS and FALS spinal cord, providing further evidence that oxidative damage may play a role in the pathogenesis of neuronal degeneration in both FALS and SALS.
Abstract: Some cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), suggesting that oxidative damage may play a role in ALS pathogenesis. To further investigate the biochemical features of FALS and sporadic ALS (SALS), we examined markers of oxidative damage to protein, lipids, and DNA in motor cortex (Brodmann area 4), parietal cortex (Brodmann area 40), and cerebellum from control subjects, FALS patients with and without known SOD mutations, SALS patients, and disease controls (Pick's disease, progressive supranuclear palsy, diffuse Lewy body disease). Protein carbonyl and nuclear DNA 8-hydroxy-2'-deoxyguanosine (OH8dG) levels were increased in SALS motor cortex but not in FALS patients. Malondialdehyde levels showed no significant changes. Immunohistochemical studies showed increased neuronal staining for hemeoxygenase-1, malondialdehyde-modified protein, and OH8dG in both SALS and FALS spinal cord. These studies therefore provide further evidence that oxidative damage may play a role in the pathogenesis of neuronal degeneration in both SALS and FALS.
792 citations
TL;DR: Patients with frontotemporal dementia with no known diagnosis of ALS or family history of ALS were clinically and electrophysiologically assessed for the presence of ALS and two had EMG findings suggestive of denervation in one limb.
Abstract: Patients with frontotemporal dementia (FTD) with no known diagnosis of ALS or family history of ALS were clinically and electrophysiologically assessed for the presence of ALS. Of 36 patients studied, five met criteria for a definite diagnosis of ALS and two had EMG findings suggestive of denervation in one limb. An additional five patients had prominent fasciculations and six other patients had trouble swallowing but all had normal results on EMG studies. One of the patients with fasciculations and a normal EMG study progressed to definite ALS over the course of 1 year.
647 citations
TL;DR: The findings suggest that G93A-mutated hSOD1 in mitochondria may cause mitochondrial defects, which contribute to precipitating the neurodegenerative process in motor neurons.
608 citations
TL;DR: A mouse model that confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease is described, and dynamitin overexpression was found to disassemble dynactin, a required activator of cytoplasmic dynein, resulting in an inhibition of retrograde axonal Transport.
552 citations
TL;DR: Anti‐inflammatory agents may have a role to play in treating ALS, and COX‐2 is a particularly attractive target because of its marked increase in ALS spinal cord.
Abstract: Neuroinflammation is a characteristic of pathologically affected tissue in several neurodegenerative disorders. These changes can be observed in the brainstem and spinal cord of amyotrophic lateral sclerosis (ALS) cases and in mouse models of the disease. They include an accumulation of large numbers of activated microglia and astrocytes, as well as small numbers of T cells, mostly adhering to postcapillary venules. Accompanying biochemical alterations include the appearance of numerous molecules characteristic of free-radical attack, the occurrence of proteins associated with activation of the complement cascade, and a sharp upregulation of the enzyme cyclooxygenase 2 (COX-2). Anti-inflammatory agents may have a role to play in treating ALS. COX-2 is a particularly attractive target because of its marked increase in ALS spinal cord.
468 citations
TL;DR: NFL is a main structural protein of axons, and it is suggested that CSF NFL can be used to monitor neurodegeneration in general, but particularly in ALS with involvement of the pyramidal tract.
Abstract: In the present study we describe an ELISA to quantify the light subunit of the neurofilament triplet protein (NFL) in CSF. The method was validated by measuring CSF NFL concentrations in healthy individuals and in two well-characterized groups of patients with amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). The levels were increased in ALS (1,743 +/- 1,661 ng/L; mean +/- SD) and AD (346 +/- 176 ng/L) compared with controls (138 +/- 31 ng/L; p < 0.0001 for both). Within the ALS group, patients with lower motor neuron signs only had lower NFL levels (360 +/- 237 ng/L) than those with signs of upper motor neuron disease (2,435 +/- 1,633 ng/L) (p < 0.05). In a second study patients with miscellaneous neurodegenerative diseases were investigated (vascular dementia, olivopontocerebellar atrophy, normal pressure hydrocephalus, cerebral infarctions, and multiple sclerosis), and the CSF NFL level was found to be increased (665 +/- 385 ng/L; p < 0.0001). NFL is a main structural protein of axons, and we suggest that CSF NFL can be used to monitor neurodegeneration in general, but particularly in ALS with involvement of the pyramidal tract.
433 citations
TL;DR: Results indicate that minocycline, which is clinically well tolerated, may represent a novel and effective drug for treatment of ALS.
420 citations
TL;DR: Oxidation of select histidine residues that bind metals in the active site mediates SOD1 aggregation and provides a plausible model to explain the accumulation of S OD1 aggregates in motor neurons affected in ALS.
340 citations
TL;DR: Using a ‘double PCR and digestion’ technique to estimate the levels of randomly distributed point mutations in two small regions of the mtDNA, it is found significantly higher levels of mutant mtDNA in the spinal cord of ALS patients compared to controls, suggesting a loss of mitochondria in ALS spinal cords.
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron death. In order to address the question of a putative role of mitochondrial dysfunction in the pathogenesis of ALS, we studied the mitochondrial DNA (mtDNA) and mitochondrial respiratory chain enzyme activities in spinal cords of ALS patients and in control subjects without neuropathologic abnormalities. Using a "double PCR and digestion" technique to estimate the levels of randomly distributed point mutations in two small regions of the mtDNA, we found significantly higher levels of mutant mtDNA in the spinal cord of ALS patients compared to controls. No large-scale rearrangements were found, but the amount of mtDNA, measured by Southern blot, was significantly lower in the ALS samples. This reduction correlated well with a decrease of citrate synthase (CS) activity, a mitochondrial marker, as were the activities of respiratory chain complexes I + III, II + III, and IV, suggesting a loss of mitochondria in ALS spinal cords.
336 citations
TL;DR: Treatment with a selective cyclooxygenase‐2 inhibitor, celecoxib, markedly inhibited production of prostaglandin E2 in the spinal cords of ALS mice, suggesting that cyclo Oxygenase-2 inhibition may benefit ALS patients.
Abstract: The pathogenesis of cell death in amyotrophic lateral sclerosis (ALS) may involve glutamate-mediated excitotoxicity, oxidative damage, and apoptosis. We used a transgenic mouse model of ALS to determine the effect of inhibition of cyclooxygenase-2 in treating the disease. Cyclooxygenase-2, present in spinal neurons and astrocytes, catalyzes the synthesis of prostaglandin E2. Prostaglandin E2 stimulates glutamate release from astrocytes, whereas cyclooxygenase-2 also plays a key role in the production of proinflammatory cytokines, reactive oxygen species, and free radicals. Treatment with a selective cyclooxygenase-2 inhibitor, celecoxib, markedly inhibited production of prostaglandin E2 in the spinal cords of ALS mice. Celecoxib treatment significantly delayed the onset of weakness and weight loss and prolonged survival by 25%. Spinal cords of treated ALS mice showed significant preservation of spinal neurons and diminished astrogliosis and microglial activation. Our results suggest that cyclooxygenase-2 inhibition may benefit ALS patients.
TL;DR: The pathobiology of neurodegenerative disorders with emphasis on genetic origin and its correlation with oxidative stress of neuro degenerative disorders will be reviewed and the reasons as to why brain constitutes a vulnerable site of oxidative damage will be discussed.
Abstract: Neurodegenerative diseases (NDD) are a group of illness with diverse clinical importance and etiologies. NDD include motor neuron disease such as amyotrophic lateral sclerosis (ALS), cerebellar disorders, Parkinson's disease (PD), Huntington's disease (HD), cortical destructive Alzheimer's disease (AD) and Schizophrenia. Numerous epidemiological and experimental studies provide many risk factors such as advanced age, genetic defects, abnormalities of antioxidant enzymes, excitotoxicity, cytoskeletal abnormalities, autoimmunity, mineral deficiencies, oxidative stress, metabolic toxicity, hypertension and other vascular disorders. Growing body of evidence implicates free radical toxicity, radical induced mutations and oxidative enzyme impairment and mitochondrial dysfunction due to congenital genetic defects in clinical manifestations of NDD. Accumulation of oxidative damage in neurons either primarily or secondarily may account for the increased incidence of NDD such as AD, ALS and stroke in aged p...
TL;DR: Results demonstrate that interference with immuno-inflammatory responses has a beneficial effect in the ALS mice model, suggesting this to be a potential new strategy to treat ALS.
Abstract: Microglial activation is thought to contribute to the progression of selective motor neuron death during amyotrophic lateral sclerosis (ALS) As minocycline has been shown to inhibit microglial activation, the therapeutic efficacy of this tetracycline derivative in the G93A mice model for familial ALS was tested This drug with proven safety delayed disease onset and dose-dependently extended the survival of the G93A mice At 120 days of age, minocycline protected mice from loss of motor neurons and from vacuolization These results demonstrate that interference with immuno-inflammatory responses has a beneficial effect in the ALS mice model, suggesting this to be a potential new strategy to treat ALS
TL;DR: There is a body of evidence implicating glutamatergic toxicity as a contributory factor in the selective neuronal injury occurring in amyotrophic lateral sclerosis (ALS) as mentioned in this paper.
Abstract: Excitotoxicity may play a role in certain disorders of the motor system thought to be caused by environmentally acquired toxins, including lathyrism and domoic acid poisoning. Motor neurons appear to be particularly susceptible to toxicity mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-kainate receptors. There is a body of evidence implicating glutamatergic toxicity as a contributory factor in the selective neuronal injury occurring in amyotrophic lateral sclerosis (ALS). Interference with glutamate-mediated toxicity is so far the only neuroprotective therapeutic strategy that has shown benefit in terms of slowing disease progression in ALS patients. Biochemical studies have shown decreased glutamate levels in central nervous system (CNS) tissue and increased levels in the cerebrospinal fluid (CSF) of ALS patients. CSF from ALS patients is toxic to neurons in culture, apparently via a mechanism involving AMPA receptor activation. There is evidence for altered expression and function of glial glutamate transporters in ALS, particularly excitatory amino acid transporter 2 (EAAT2). Abnormal splice variants of EAAT2 have been detected in human CNS. Mitochondrial dysfunction may contribute to excitotoxicity in ALS. Induction of neuronal nitric oxide synthase and cyclooxygenase 2 in ALS may also lead to significant interactions with regulation of the glutamate transmitter system. Certain features of motor neurons may predispose them to the neurodegenerative process in ALS, such as the cell size, mitochondrial activity, neurofilament content, and relative lack of certain calcium-binding proteins and molecular chaperones. Motor neurons appear vulnerable to toxicity mediated by calcium-permeable AMPA receptors. The relatively low expression of the glutamate receptor 2 (GluR2) AMPA receptor subunit and the high current density caused by the large number and density of cell surface AMPA receptors are potentially important factors that may predispose to such toxicity.
TL;DR: The function of SOD under normal physiological conditions as well as its role in the cellular and molecular mechanisms underlying oxidative tissue damage and neurological abnormalities are summarized.
Abstract: In recent years, oxidative stress has been implicated in a variety of degenerative processes, diseases, and syndromes. Some of these include atherosclerosis, myocardial infarction, stroke, and ischemia/reperfusion injury; chronic and acute inflammatory conditions such as wound healing; central nervous system disorders such as forms of familial amyotrophic lateral sclerosis (ALS) and glutathione peroxidase-linked adolescent seizures; Parkinson's disease and Alzheimer's dementia; and a variety of other age-related disorders. Among the various biochemical events associated with these conditions, emerging evidence suggests the formation of superoxide anion and expression/activity of its endogenous scavenger, superoxide dismutase (SOD), as a common denominator. This review summarizes the function of SOD under normal physiological conditions as well as its role in the cellular and molecular mechanisms underlying oxidative tissue damage and neurological abnormalities. Experimental evidence from laboratory animals that either overexpress (transgenics) or are deficient (knockouts) in antioxidant enzyme/protein levels and the genetic SOD mutations observed in some familial cases of ALS are also discussed.
TL;DR: It is concluded that one important mechanism by which mutant SOD1 causes motor neurone injury involves inhibition of specific components of the mitochondrial electron transfer chain.
Abstract: The molecular mechanisms by which mutations in the gene for Cu/Zn superoxide dismutase (SOD1) lead to the selective death of motor neurones in familial amyotrophic lateral sclerosis (FALS) remain incompletely understood. Previous evidence has indicated that mitochondrial abnormalities may develop during motor neurone injury, but several important questions remain unanswered. We have developed a cell culture model of FALS in which a motor neurone cell line (NSC34) has been stably transfected to express normal or mutant human SOD1 at levels approximating to those seen in the human disease. The aims of the study were to: (i) investigate whether morphological mitochondrial abnormalities occur at expression levels of mutant SOD1 close to physiological levels; and (ii) determine whether the presence of mutant SOD1 causes abnormalities of mitochondrial respiratory chain function and changes in cellular bioenergetic parameters in motor neuronal cells. Using this cellular model, we demonstrate that the presence of mutant SOD1 results in the development of abnormally swollen and pale staining mitochondria. These morphological changes are accompanied by biochemical abnormalities with specific decreases in the activities of complexes II and IV of the mitochondrial electron transfer chain. These same complexes are inhibited when control NSC34 cells are subjected to oxidative stress induced by serum withdrawal. The decrease in respiratory chain complex activity in the presence of mutant SOD1 was not accompanied by decreased expression of representative proteins present in these complexes. Motor neuronal cells expressing mutant SOD1 showed increased cell death when exposed to oxidative stress by serum withdrawal, whereas the presence of normal human SOD1 exerted a protective effect. Under basal, unstressed culture conditions, no change in the ATP : ADP ratio was observed in the presence of mutant SOD1. However, the mitochondrial changes associated with the presence of mutant SOD1 clearly had adverse cellular bioenergetic consequences as shown by increased cell death in the presence of pharmacological inhibition of the glycolytic pathway. We conclude that one important mechanism by which mutant SOD1 causes motor neurone injury involves inhibition of specific components of the mitochondrial electron transfer chain. Therapeutic measures aimed at protecting mitochondrial respiratory chain function may be useful in SOD1 related familial and possibly other forms of amyotrophic lateral sclerosis.
TL;DR: In this paper, the molecular mechanism underlying motor neuron degeneration in the transgenic mouse model expressing the SOD1 gene with G93A mutation was analyzed using cDNA microarray.
Abstract: Familial amyotrophic lateral sclerosis (FALS)-linked mutations in copper-zinc superoxide dismutase (SOD1) cause motor neuron death through one or more acquired toxic properties. We analyzed the molecular mechanism underlying motor neuron degeneration in the transgenic mouse model expressing the SOD1 gene with G93A mutation. Using cDNA microarray, the differentially expressed genes were identified in the spinal cords of G93A mice, 30 being elevated and seven decreased. cDNA microarray analysis to monitor gene expression during neurodegeneration revealed an up-regulation of genes related to an inflammatory process, such as the tumor necrosis factor-alpha (TNF-alpha) gene, resulting from glial cell activation, together with the change in apoptosis-related gene expression, such as caspase-1. The increased expression of the inflammation- and apoptosis-related genes occurred at 11 weeks of age in the presymptomatic stage prior to motor neuron death. These results suggest a mechanism of neurodegeneration that includes an inflammatory response as an important component. Thus, ALS has paralleled other neurodegenerative disorders, such as Alzheimer's and prion diseases, in which the inflammatory process is believed to participate directly in neuronal death.
TL;DR: It is shown here that AAV-GDNF leads to substantial and long-lasting expression of transgenic GDNF in a large number of myofibers with its accumulation at the sites of neuromuscular junctions, indicating that A AV-mediated GDNF delivery to the muscle is a promising means of gene therapy for ALS.
Abstract: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive lethal disease that involves selective annihilation of motoneurons. Glial cell line-derived neurotrophic factor (GDNF) is proposed to be a promising therapeutic agent for ALS and other motor neuron diseases. Because adeno-associated virus (AAV) has been developed as an attractive gene delivery system with proven safety, we explored the therapeutic efficacy of intramuscular delivery of the GDNF gene mediated by an AAV vector (AAV-GDNF) in the G93A mouse model of ALS. We show here that AAV-GDNF leads to substantial and long-lasting expression of transgenic GDNF in a large number of myofibers with its accumulation at the sites of neuromuscular junctions. Detection of GDNF labeled with FLAG in the anterior horn neurons, but not β-galactosidase expressed as a control, indicates that most of the transgenic GDNF observed there is retrogradely transported GDNF protein from the transduced muscles. This transgenic GDNF prevents motoneurons from their degeneration, preserves their axons innervating the muscle, and inhibits the treated-muscle atrophy. Furthermore, four-limb injection of AAV-GDNF postpones the disease onset, delays the progression of the motor dysfunction, and prolongs the life span in the treated ALS mice. Our finding thus indicates that AAV-mediated GDNF delivery to the muscle is a promising means of gene therapy for ALS.
TL;DR: High glutamate concentrations were correlated with a spinal onset of the disease, more impaired limb function and a higher rate of muscle deterioration, suggesting that elevations of CSF glutamate concentrations could reflect the intensity of cell insult in the spinal cord.
TL;DR: In ALS patients and Cu/Zn‐SOD mutant mice, increased oxidative stress occurs in association with the lipid alterations, and exposure of cultured motor neurons to oxidative stress increases the accumulation of sphingomyelin, ceramides, and cholesterol esters.
Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons in the spinal cord resulting in progressive paralysis and death. The pathogenic mechanism of ALS is unknown but may involve increased oxidative stress, overactivation of glutamate receptors, and apoptosis. We report abnormalities in sphingolipid and cholesterol metabolism in the spinal cords of ALS patients and in a transgenic mouse model (Cu/ZnSOD mutant mice), which manifest increased levels of sphingomyelin, ceramides, and cholesterol esters; in the Cu/ZnSOD mutant mice, these abnormalities precede the clinical phenotype. In ALS patients and Cu/Zn-SOD mutant mice, increased oxidative stress occurs in association with the lipid alterations, and exposure of cultured motor neurons to oxidative stress increases the accumulation of sphingomyelin, ceramides, and cholesterol esters. Pharmacological inhibition of sphingolipid synthesis prevents accumulation of ceramides, sphingomyelin, and cholesterol esters and protects motor neurons against death induced by oxidative and excitotoxic insults. These findings suggest a pivotal role for altered sphingolipid metabolism in the pathogenesis of ALS.
TL;DR: The use of genetically engineered mouse models that are instrumental for understanding why AD is a neuronal disease, and for validating attractive therapeutic targets, are emphasized.
Abstract: Recent research has significantly advanced our understanding of the molecular mechanisms of neurodegenerative diseases, including Alzheimer's disease (AD) and motor neuron disease. Here we emphasize the use of genetically engineered mouse models that are instrumental for understanding why AD is a neuronal disease, and for validating attractive therapeutic targets. In motor neuron diseases, Cu/Zn superoxide dismutase and survival motor neuron mouse models are useful in testing disease mechanisms and therapeutic strategies for amyotrophic lateral sclerosis (ALS) and spinal motor atrophy, respectively, but the mechanisms that account for selective motor neuron loss remain uncertain. We anticipate that, in the future, therapies based on understanding disease mechanisms will be identified and tested in mouse model systems.
TL;DR: It is demonstrated that the entry of SOD1 into mitochondria depends on demetallation and that heat shock proteins block the uptake of the FALS-associated mutant S OD1 (G37R, G41D, or G93A), while having no effect on wild-type SOD 1.
Abstract: Missense mutations in Cu,Zn-superoxide dismutase (SOD1) account for ≈20% of familial amyotrophic lateral sclerosis (FALS) through some, as yet undefined, toxic gain of function that leads to gradual death of motor neurons Mitochondrial swelling and vacuolization are early signs of incipient motor neuron death in FALS We previously reported that SOD1 exists in the intermembrane space of mitochondria Herein, we demonstrate that the entry of SOD1 into mitochondria depends on demetallation and that heat shock proteins (Hsp70, Hsp27, or Hsp25) block the uptake of the FALS-associated mutant SOD1 (G37R, G41D, or G93A), while having no effect on wild-type SOD1 The binding of mutant SOD1 to Hsps in the extract of neuroblastoma cells leads to formation of sedimentable aggregates Many antiapoptotic effects of Hsps have been reported We now propose that this binding of Hsps to mutant forms of a protein abundant in motor neurons, such as SOD1, makes Hsps unavailable for their antiapoptotic functions and leads ultimately to motor neuron death It also appears that the Hsp–SOD1 complex recruits other proteins present in the neuroblastoma cell and presumably in motor neurons to form sedimentable aggregates
Journal Article•
TL;DR: The present review describes the role of SODs, especially Cu, Zn SOD, in several diseases, such as familial amyotrophic lateral sclerosis (FALS), Parkinson's disease, Alzheimer's Disease, dengue fever, cancer, Down's syndrome, cataract, and several neurological disorders.
Abstract: Reactive oxygen species, such as superoxide radicals, are thought to underlie the pathogenesis of various diseases. Almost 3 to 10% of the oxygen utilized by tissues is converted to its reactive intermediates, which impair the functioning of cells and tissues. Superoxide dismutase (SOD) catalyzes the conversion of single electron reduced species of molecular oxygen to hydrogen peroxide and oxygen. There are several classes of SOD that differ in their metal binding ability, distribution in different cell compartments, and sensitivity to various reagents. Among these, Cu, Zn superoxide dismutase (SOD1) is widely distributed and comprises 90% of the total SOD. This ubiquitous enzyme, which requires Cu and Zn for its activity, has great physiological significance and therapeutic potential. The present review describes the role of SODs, especially Cu, Zn SOD, in several diseases, such as familial amyotrophic lateral sclerosis (FALS), Parkinson's disease, Alzheimer's disease, dengue fever, cancer, Down's syndrome, cataract, and several neurological disorders. Mutations in the SOD1 gene cause a familial form of amyotrophic lateral sclerosis. The mechanism by which mutant SOD1 causes the degeneration of motor neurons is not well understood. Transgenic mice expressing multiple copies of FALS-mutant SOD1s develop an ALS-like motor neuron disease. Vacuolar degeneration of mitochondria has been identified as the main pathological feature associated with motor neuron death and paralysis in several lines of FALS-SOD1 mice. Various observations and conclusions linking mutant SOD1 and FALS are discussed in this review in detail.
TL;DR: There has become evident that there is considerable interplay between these mechanisms and, as the role of each is established, a common picture may emerge, enabling the development of more targeted therapies.
Abstract: The increasing complexity of the pathways implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS) has stimulated intensive research in many directions. Genetic analysis of familial ALS has yielded six loci and one disease gene (SOD1), initially suggesting a role for free radicals in the disease process, although the mechanisms through which the mutant exerts toxicity and results in selective motor neuron death remain uncertain. Numerous studies have focused on structural elements of the affected cell, emphasizing the role of neurofilaments and peripherin and their functional disruption in disease. Other topics examined include cellular homeostasis of copper and calcium, particularly in the context of oxidative stress and the processes of protein aggregation, glutamate excitotoxicity, and apoptosis. It has become evident that there is considerable interplay between these mechanisms and, as the role of each is established, a common picture may emerge, enabling the development of more targeted therapies. This study discusses the main areas of investigation and reviews the findings.
TL;DR: A retrospective study to compare survival factors with disease progression in a German ALS population and found that the declines of ALS‐FRS, FVC%, and MRC compound score were predictive of survival.
Abstract: Predicting the rate of disease progression has become important as trials of new medical treatments for amyotrophic lateral sclerosis (ALS) are planned. Bulbar onset, early impairment of forced vital capacity, and older age have all been associated with shorter survival. We performed a retrospective study to compare survival factors with disease progression in a German ALS population. We analyzed disease progression in 155 patients at intervals of 4 months over a period of 3 years. To evaluate disease progression, the ALS functional rating scale (ALS-FRS), forced vital capacity (FVC%), and a Medical Research Council (MRC) compound score based on a nine-step modified MRC scale were used. We compared age ( or =55 years), different sites of disease onset (bulbar vs. limb), and gender to the rate of disease progression and performed survival analyses. No overall significant difference could be detected when analyzing these subgroups with regard to disease progression. By contrast, significantly longer survival was observed in the younger age group (56 months vs. 38 months, P < 0.0001) and in patients with limb-onset disease (51 months vs. 37 months, P = 0.0002). Using Cox analyses values we found that the declines of ALS-FRS, FVC%, and MRC compound score were predictive of survival (P < 0.0001, P = 0.002, and P = 0.003, respectively). Future studies are needed to clarify whether nonspecific factors including muscle atrophy, dysphagia, and coexisting diseases influence prediction of survival in ALS patients. A more precise set of predictors may help to better stratify patient subgroups for future treatment trials.
TL;DR: How mitochondrial dysfunction could be of relevance in ALS and the evidence that an alteration of mitochondrial function is a feature of the disease are discussed.
TL;DR: A functional defect in mitochondria in the ventral horn region is demonstrated and the view that mitochondrial damage plays a role in mutant SOD1‐induced motoneuron degeneration pathway is supported.
Abstract: Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that causes degeneration of motoneurons. Mutation of Cu,Zn superoxide dismutase (SOD1) is one cause for this disease. In mice, expression of mutant protein causes motoneuron degeneration and paralysis resembling the human disease. Morphological change, indicative of mitochondrial damage, occurs at early stages of the disease. To determine whether mitochondrial function changes during the course of disease progression, enzyme activities of mitochondrial electron transport chain in spinal cords from mice at different disease stages were measured using three different methods: spectrophotometric assay, in situ histochemical enzyme assay, and blue native gel electrophoresis combined with in-gel histochemical reaction. The enzyme activities were decreased in the spinal cord, particularly in the ventral horn, beginning at early disease stages. This decrease persisted throughout the course of disease progression. This decrease was not detected in the spinal cords of non-transgenic animals, of mice expressing the wild-type protein, and in cerebellum and dorsal horn of the spinal cords from mice expressing mutant protein. These results demonstrate a functional defect in mitochondria in the ventral horn region and support the view that mitochondrial damage plays a role in mutant SOD1-induced motoneuron degeneration pathway.
TL;DR: It is shown that AVR-mediated GDNF expression delayed the onset of disease by 7 +/- 8 days, prolonged survival by 17 +/- 10 days, and delayed the decline in motor functions (as determined on a rotating rod) by 7-14 days.
Abstract: Amyotrophic lateral sclerosis (ALS) is caused by a progressive degeneration of motor neurons. The cause of sporadic ALS is not known, but 1–2% of all cases are familial and caused by mutations in the copper–zinc superoxide dismutase (SOD1) gene. Transgenic SOD1 mice serve as a transgenic mouse model for these cases. Glial cell-derived neurotrophic factor (GDNF) has a potent trophic effect on motor neurons. Clinical trials in which growth factors have been systemically administered to ALS patients have not been effective, owing in part to the short half-life of these factors and their low concentrations at target sites. Gene transfer of therapeutic factors to motor neurons and/or their target cells, such as muscle, may overcome these problems. Previously, we and others have shown that intramuscularly administered adenovirus vector (AVR) results in foreign gene expression not only in muscle cells, but also in relevant motor neurons in the spinal cord, because of retrograde axonal transport. In this study we...
TL;DR: If, as seems likely, complex inherited and environmental factors contribute to the pathogenesis of MND, future treatment may involve a combination of molecular based treatments or restoration of cellular integrity using stem cell grafts.
Abstract: Motor neurone disease (MND), or amyotrophic lateral sclerosis (ALS), is a neurodegenerative disorder of unknown aetiology. Progressive motor weakness and bulbar dysfunction lead to premature death, usually from respiratory failure. Confirming the diagnosis may initially be difficult until the full clinical features are manifest. For all forms of the disease there is a significant differential diagnosis to consider, including treatable conditions, and therefore specialist neurological opinion should always be sought. Clear genetic inheritance has been demonstrated in a minority of patients with familial ALS but elucidation of the biological basis of genetic subtypes is also providing important information which may lead to treatments for sporadic forms of the disease. In the absence of curative or disease modifying therapy, management is supportive and requires a multidisciplinary approach. If, as seems likely, complex inherited and environmental factors contribute to the pathogenesis of MND, future treatment may involve a combination of molecular based treatments or restoration of cellular integrity using stem cell grafts.
TL;DR: In vivo evidence is provided that expression of mutations in SOD1 can lead to increased generation of “hydroxyl radical‐like” activity, which further implicates oxidative damage in the pathogenesis of ALS.
Abstract: Mutations in the enzyme copper/zinc superoxide dismutase-1 (SOD1) are associated with familial amyotrophic lateral sclerosis (FALS). The means by which the mutations cause FALS appears to be due to an adverse property of the mutant SOD1 protein that may involve increased generation of free radicals. We used in vivo microdialysis to measure the conversion of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid (3,4-DHBA) as a measure of “hydroxyl radical-like” production in transgenic amyotrophic lateral sclerosis (ALS) mice with the G93A mutation as well as littermate controls. The conversion of 4-hydroxybenzoic acid to 3,4-DHBA was significantly increased in the striatum of transgenic ALS mice at baseline but not in mice overexpressing wild-type human SOD1. Following administration of 3-nitropropionic acid 3,4-DHBA generation was significantly increased as compared with baseline, and the increase in the transgenic ALS mice was significantly greater than those in controls, whereas the increase in mice overexpressing wild-type human SOD1 was significantly attenuated. The present results provide in vivo evidence that expression of mutations in SOD1 can lead to increased generation of “hydroxyl radical-like” activity, which further implicates oxidative damage in the pathogenesis of ALS.