Showing papers on "Amyotrophic lateral sclerosis published in 2003"
TL;DR: Nonneuronal cells that do not express mutant SOD1 delay degeneration and significantly extend survival of mutant-expressing motor neurons.
Abstract: The most common inherited [correct] form of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting adult motor neurons, is caused by dominant mutations in the ubiquitously expressed Cu-Zn superoxide dismutase (SOD1) In chimeric mice that are mixtures of normal and SOD1 mutant-expressing cells, toxicity to motor neurons is shown to require damage from mutant SOD1 acting within nonneuronal cells Normal motor neurons in SOD1 mutant chimeras develop aspects of ALS pathology Most important, nonneuronal cells that do not express mutant SOD1 delay degeneration and significantly extend survival of mutant-expressing motor neurons
1,107 citations
TL;DR: It is reported that insulin-like growth factor 1 prolongs life and delays disease progression, even when delivered at the time of overt disease symptoms.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neuromuscular disease that is associated with the degeneration of spinal and brainstem motor neurons, leading to atrophy of limb, axial, and respiratory muscles. The cause of ALS is unknown, and there is no effective therapy. Neurotrophic factors are candidates for therapeutic evaluation in ALS. Although chronic delivery of molecules to the central nervous system has proven difficult, we recently discovered that adeno-associated virus can be retrogradely transported efficiently from muscle to motor neurons of the spinal cord. We report that insulin-like growth factor 1 prolongs life and delays disease progression, even when delivered at the time of overt disease symptoms.
904 citations
TL;DR: It is shown that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology.
Abstract: Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.
695 citations
TL;DR: Some of the properties of both wild-type and mutant CuZnSOD proteins are reviewed, suggests how these properties may be relevant to these two hypotheses, and proposes that these two hypothesis are not necessarily mutually exclusive.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of motor neurons. The inherited form of the disease, familial ALS, represents 5–10% of the total cases, and the best documented of these are due to lesions in SOD1, the gene encoding copper–zinc superoxide dismutase (CuZnSOD). The mechanism by which mutations in SOD1 cause familial ALS is currently unknown. Two hypotheses have dominated recent discussion of the toxicity of ALS mutant CuZnSOD proteins: the oligomerization hypothesis and the oxidative damage hypothesis. The oligomerization hypothesis maintains that mutant CuZnSOD proteins are, or become, misfolded and consequently oligomerize into increasingly high-molecular-weight species that ultimately lead to the death of motor neurons. The oxidative damage hypothesis maintains that ALS mutant CuZnSOD proteins catalyze oxidative reactions that damage substrates critical for viability of the affected cells. This perspective reviews some of the properties of both wild-type and mutant CuZnSOD proteins, suggests how these properties may be relevant to these two hypotheses, and proposes that these two hypotheses are not necessarily mutually exclusive.
521 citations
TL;DR: Increased levels of 4-hydroxynonenal in neurodegenerative disorders and immunohistochemical distribution of HNE in brain tissue indicate pathophysiological role of oxidative stress in these diseases, and especially H NE in formation of abnormal filament deposites.
313 citations
TL;DR: Cord blood transfusion into the systemic circulation of G93A mice delayed disease progression at least 2-3 weeks and increased lifespan of diseased mice, indicating that cord blood may have therapeutic potential in this noninvasive cell-based treatment of ALS.
Abstract: Amyotrophic lateral sclerosis (ALS), a multifactorial disease characterized by diffuse motor neuron degeneration, has proven to be a difficult target for stem cell therapy. The primary aim of this study was to determine the long-term effects of intravenous mononuclear human umbilical cord blood cells on disease progression in a well-defined mouse model of ALS. In addition, we rigorously examined the distribution of transplanted cells inside and outside the central nervous system (CNS), migration of transplanted cells to degenerating areas in the brain and spinal cord, and their immunophenotype. Human umbilical cord blood (hUCB) cells (106) were delivered intravenously into presymptomatic G93A mice. The major findings in our study were that cord blood transfusion into the systemic circulation of G93A mice delayed disease progression at least 2–3 weeks and increased lifespan of diseased mice. In addition, transplanted cells survived 10–12 weeks after infusion while they entered regions of motor neuron degen...
307 citations
TL;DR: It is concluded that patients with SOD1 mutations may infrequently show symptoms and signs unrelated to the motor systems, sometimes obscuring the diagnosis of ALS.
Abstract: OBJECTIVE: Since the discovery of mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) ten years ago, testing for SOD1 gene mutations has become a part of the investigation of patients with suspected motor neuron disease. We searched for novel SOD1 mutations and for clinical characteristics of patients with these mutations.METHODS: Analysis was made of patient files at the Neurogenetic DNA Diagnostic Laboratory at Massachusetts General Hospital. We also scrutinized available medical records and examined patients with the different SOD1 mutations.RESULTS: One hundred and forty eight (148) of 2045 amyotrophic lateral sclerosis (ALS) patients carried a disease‐associated mutation in the SOD1 gene. The most prevalent was the A4V missense mutation, found in 41% of those patients. Sixteen novel exonic mutations (L8V, F20C, Q22L, H48R, T54R, S59I, V87A, T88ΔTAD, A89T, V97M, S105ΔSL, V118L, D124G, G141X, G147R, I151S) were found, bringing the total number of SOD1 gene mutations in ALS to 105.CONCLUSIO...
279 citations
TL;DR: The results suggest that the loss of EAAT2 may contribute to, but does not cause, motor neuron degeneration in ALS.
Abstract: The glial glutamate transporter EAAT2 is primarily responsible for clearance of glutamate from the synaptic cleft and loss of EAAT2 has been previously reported in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. The loss of functional EAAT2 could lead to the accumulation of extracellular glutamate, resulting in cell death known as excitotoxicity. However, it is still unknown whether it is a primary cause in the cascade leading to neuron degeneration or a secondary event to cell death. The goals of this study were to generate transgenic mice overexpressing EAAT2 and then to cross these mice with the ALS-associated mutant SOD1(G93A) mice to investigate whether supplementation of the loss of EAAT2 would delay or rescue the disease progression. We show that the amount of EAAT2 protein and the associated Na+-dependent glutamate uptake was increased about 2-fold in our EAAT2 transgenic mice. The transgenic EAAT2 protein was properly localized to the cell surface on the plasma membrane. Increased EAAT2 expression protects neurons from L-glutamate induced cytotoxicity and cell death in vitro. Furthermore, our EAAT2/G93A double transgenic mice showed a statistically significant (14 days) delay in grip strength decline but not in the onset of paralysis, body weight decline or life span when compared with G93A littermates. Moreover, a delay in the loss of motor neurons and their axonal morphologies as well as other events including caspase-3 activation and SOD1 aggregation were also observed. These results suggest that the loss of EAAT2 may contribute to, but does not cause, motor neuron degeneration in ALS.
275 citations
TL;DR: The biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed and particular emphasis will be given to the role played by the nuclear transcription factor -kB (NF-kB) in apoptosis, and in the pathogenesis of neurodegenersative disorders, such as AD, PD, and ALS.
Abstract: Aging is a major risk factor for neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to oxidative stress which can induce neuronal damage, ultimately leading to neuronal death by apoptosis or necrosis. A large body of evidence indicates that oxidative stress is involved in the pathogenesis of AD, PD, and ALS. Several studies have shown that nutritional antioxidants (especially vitamin E and polyphenols) can block neuronal death in vitro, and may have therapeutic properties in animal models of neurodegenerative diseases including AD, PD, and ALS. Morever, clinical data suggest that nutritional antioxidants might exert some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed. Particular emphasis will be given to the role played by the nuclear transcription factor -kB (NF-kB) in apoptosis, and in the pathogenesis of neurodegenenerative disorders, such as AD, PD, and ALS. The effects of ROS and antioxidants on NF-kB function and their relevance in the pathophysiology of neurodegenerative diseases will also be examined. Keyword: neurodegeneration, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, oxidative stress, nuclear factor kB, antioxidants, polyphenols, neuroprotection, nutritional.
273 citations
TL;DR: A patient presenting with PMA with rapid clinical evolution likely has the pathology and pathophysiology of ALS whether or not upper motor neuron signs evolve.
Abstract: Objective: Examining the unresolved relationship between the lower motor neuron disorder progressive muscular atrophy (PMA) and ALS is important in clinical practice because of emerging therapies. Methods: Spinal and brainstem tissues donated from patients with ALS/motor neuron disorder (n = 81) were examined. Using retrospective case note review, the authors assigned patients into three categories: PMA (12), PMA progressing to ALS (6), and ALS ab initio (63). Conventional stains for long tract degeneration and immunocytochemistry for ubiquitin and the macrophage marker CD68 were examined. Results: Rapid progression and typical ubiquitinated inclusions in lower motor neurons were present in 77 (95%) of the cases. Immunocytochemistry for CD68 was a more sensitive marker of long tract pathology in comparison with conventional stains. Half of the cases with PMA showed corticospinal tract degeneration by CD68. Conclusion: Patients with PMA frequently have undetected long tract pathology and most have ubiquitinated inclusions typical of ALS. A patient presenting with PMA with rapid clinical evolution likely has the pathology and pathophysiology of ALS whether or not upper motor neuron signs evolve.
272 citations
Journal Article•
TL;DR: A recent article published in Neurology raises a concern for migraineurs who have concomitant restless legs syndrome (RLS), and suggests that droperidol or haloperidol could in fact be used as a diagnostic challenge, but the severity of some reactions would mitigate against this use.
Abstract: To the Editor: A recent article published in Neurology raises a concern for migraineurs who have concomitant restless legs syndrome (RLS).1 Because RLS—similar to and often conflated with akathisia—is quite common (affecting about 10% of the population), assuming no interaction between the two conditions (possibly an incorrect assumption), 1 to 2% of the population would be expected to have both migraine and RLS. Because migraine is maximally expressed in 20to 40-year-old women, while RLS is predominant after age 45 years (with several studies showing a 3:2 women:men ratio), the actual rate of comorbidity in the target age range for typical migraine may be less than 1% of the total population (or, 10% of migraineurs). Further, the average age at onset in primary (familial) RLS, accounting for about half the patients, is about 30 years, but age at diagnosis averages 40 years, indicating that in the target age group for most migraineurs, the diagnosis of RLS is unlikely to have yet been uncovered, although its presence might nevertheless be a clinical burden for the patient. In their table 3, Silberstein et al. indicate that 31% of the patients who received droperidol developed akathisia.1 This reaction could be an expected exacerbation of underlying RLS. It is well established that dopamine agonists are the most effective treatment for the core symptoms of RLS. On the other hand, droperidol is one of the most potent blockers of D2 (and D3?) receptors, and these are the same receptors for which the current fist-line RLS drugs—ropinirole and pramipexole—have the most potent agonist effects. A closer look brings up an interesting point. Noting that actual proportion of patients having akathisia was more than double the high-end estimate of expected RLS, and if in fact the observed akathisia does represent RLS, one is led to speculate that either the specific migraine group chosen for this study was unusually prone to RLS (perhaps a portion of their headache intractability is related to undiagnosed RLS and an attendant sleep disorder) or the migraine population in general harbors a higher than expected rate of RLS comorbidity. In favor of the latter are unpublished sleep laboratory data showing that, of 131 patients who had a polysomnogram (out of a total headache clinic population of 289), 45% had greater than 10/hour periodic leg movements, a finding that, although not diagnostic of RLS, is considered supportive when other RLS symptoms are present (and when not, indicates a likely diagnosis of periodic limb movement disorder of sleep [PLMD], a disorder that also responds to dopamine agonists). By comparison, the rate of PLMD increases with age and in those over 65 years of age it is 30%. One obvious question is as follows: Why has this issue of RLS induced by dopamine blockers not been raised in the past? The fact is that it has, but perhaps not broadly enough. If one looks in the anesthesia literature—where droperidol is likely to be used— one finds a bit more about the untoward side-effects of widespread dopamine blockage in the RLS patient.2 Another article described the severe bout of RLS that can result from the use of prochlorperazine, now being employed somewhat more often for migraine, but still used most frequently for its original indication—nausea.3 Many patients who eventually are diagnosed with RLS are initially unaware of the connection between their urge to move and the chronic condition called RLS. Droperidol or haloperidol could in fact be used as a diagnostic challenge, but the severity of some reactions would mitigate against this use unless the protocol called for starting with very small doses and gradually building up. One recommendation for avoiding having to deal with this problem in the emergency department would be to pre-empt it in the headache, by screening for RLS. If the RLS patients are known, then strategies can be developed to provide alternative emergency room treatments for them. For a brief overview of RLS and its diagnostic criteria, see the home page of the RLS Foundation’s web site at http://www.rls.org. For a more comprehensive review of RLS we recommend the RLS Medical Bulletin, which has recently (for 2003) undergone extensive review and expansion. Until it is mounted on the Web site (in place of 2001 version), the new rendition can be obtained—free of charge for physicians— from the RLS Foundation.
TL;DR: The results indicate that the high threshold for induction of the stress response in motor neurons stems from an impaired ability to activate the main heat shock–stress sensor, HSF1.
Abstract: Heat shock protein 70 (Hsp70) protects cultured motor neurons from the toxic effects of mutations in Cu/Zn-superoxide dismutase (SOD-1), which is responsible for a familial form of the disease, amyotrophic lateral sclerosis (ALS). Here, the endogenous heat shock response of motor neurons was investigated to determine whether a high threshold for activating this protective mechanism contributes to their vulnerability to stresses associated with ALS. When heat shocked, cultured motor neurons failed to express Hsp70 or transactivate a green fluorescent protein reporter gene driven by the Hsp70 promoter, although Hsp70 was induced in glial cells. No increase in Hsp70 occurred in motor neurons after exposure to excitotoxic glutamate or expression of mutant SOD-1 with a glycine--> alanine substitution at residue 93 (G93A), nor was Hsp70 increased in spinal cords of G93A SOD-1 transgenic mice or sporadic or familial ALS patients. In contrast, strong Hsp70 induction occurred in motor neurons with expression of a constitutively active form of heat shock transcription factor (HSF)-1 or when proteasome activity was sufficiently inhibited to induce accumulation of an alternative transcription factor HSF2. These results indicate that the high threshold for induction of the stress response in motor neurons stems from an impaired ability to activate the main heat shock-stress sensor, HSF1.
TL;DR: These findings demonstrate that mutant SOD1, possibly by toxicity associated with its aggregation, causes mitochondrial degeneration by inducing extension and leakage of the outer mitochondrial membrane, and expansion of the intermembrane space.
Abstract: Background
Amyotrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disease that causes motor neuron degeneration, paralysis and death. Mutations in Cu, Zn superoxide dismutase (SOD1) are one cause for the familial form of this disease. Transgenic mice expressing mutant SOD1 develop age-dependent motor neuron degeneration, skeletal muscle weakness, paralysis and death similar to humans. The mechanism whereby mutant SOD1 induces motor neuron degeneration is not understood but widespread mitochondrial vacuolation has been observed during early phases of motor neuron degeneration. How this vacuolation develops is not clear, but could involve autophagic vacuolation, mitochondrial permeability transition (MPT) or uncharacterized mechanisms. To determine which of these possibilities are true, we examined the vacuolar patterns in detail in transgenic mice expressing mutant SOD1G93A.
TL;DR: The results appear to demonstrate that the procedures of ex vivo expansion of autologous mesenchymal stem cells and of transplantation into the spinal cord of humans are safe and well tolerated by ALS patients.
Abstract: INTRODUCTION: Recently it has been shown in animal models of amyotrophic lateral sclerosis (ALS) that stem cells significantly slow the progression of the disease and prolong survival. We have evaluated the feasibility and safety of a method of intraspinal cord implantation of autologous mesenchymal stem cells (MSCs) in a few well‐monitored patients with ALS.METHOD: Bone marrow collection was performed according to the standard procedure by aspiration from the posterior iliac crest. Ex vivo expansion of mesenchymal stem cells was induced according to Pittenger's protocol. The cells were suspended in 2 ml of autologous cerebrospinal fluid and transplanted into the spinal cord by a micrometric pump injector.RESULTS: No patient manifested major adverse events such as respiratory failure or death. Minor adverse events were intercostal pain irradiation (4 patients) which was reversible after a mean period of three days after surgery, and leg sensory dysesthesia (5 patients) which was reversible after a mean pe...
TL;DR: The studies show that vaccination significantly improved motor activity and suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death.
Abstract: Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu/Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 ± 7 days (n = 15) to 263 ± 8 days (n = 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of protective autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.
TL;DR: This review focuses on existing evidence that oxidative stress is a major culprit in the pathogenesis of amyotrophic lateral sclerosis and examines whether metal-mediated oxidative stress would lead to several intracellular alterations and contribute to the induction of cell death pathways.
TL;DR: The results suggest that combinations of therapies targeting different disease mechanisms may be a useful strategy in the treatment of ALS.
Abstract: There is substantial evidence implicating both inflammation and mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS) pathogenesis. We investigated the therapeutic effects of cyclooxygenase 2 (COX-2) inhibitors both alone and in combination with creatine in the G93A transgenic mouse model of ALS. Oral administration of either celecoxib or rofecoxib significantly improved motor performance, attenuated weight loss and extended survival. The administration of COX-2 inhibitors significantly reduced prostaglandin E2 levels at 110 days of age. The combination of creatine with COX-2 inhibitors produced additive neuroprotective effects and extended survival by approximately 30%. The COX-2 inhibitors significantly protected against depletion of anterior horn motor neurons and creatine with COX-2 inhibitors showed greater protection than COX-2 inhibitors alone. These results suggest that combinations of therapies targeting different disease mechanisms may be a useful strategy in the treatment of ALS.
TL;DR: Activation of p38MAPK in motor neurons and then in reactive glial cells may contribute, respectively, to the development and progression of motor neuron pathology in SOD1G93A mice.
TL;DR: The clinical and pathological expressions of ALS are almost indistinguishable between the familial and sporadic forms, although often in the former the age at onset is younger, the course of the disease more rapid, and the survival after diagnosis shorter.
Abstract: Amyotrophic lateral sclerosis (ALS) is a relentless fatal paralytic disorder confined to the voluntary motor system (1). Its prevalence is about three to five in 100,000 individuals, making it the most frequent paralytic disease in adults. Although ALS can strike anyone at any age, generally the onset of the disease is in the fourth or fifth decade of life. Common clinical features of ALS include muscle weakness, fasciculations, brisk (or depressed) reflexes, and extensor plantar responses. Even though motor deficit usually predominates in the limbs, bulbar enervation can also be severely affected, leading to atrophy of the tongue, dysphagia, and dysarthria. Other cranial nerves (e.g., oculomotor nerves) are usually spared. The progressive decline of muscular function results in paralysis, speech and swallowing disabilities, emotional disturbance, and, ultimately, respiratory failure causing death among the vast majority of ALS patients within 2–5 years after the onset of the disease. Pathologically, ALS is characterized by a loss of upper motor neurons in the cerebral cortex and of the lower motor neurons in the spinal cord. Often, there is also a profound degeneration of the corticospinal tracts, which is most evident at the level of the spinal cord. The few remaining motor neurons are generally atrophic, and many demonstrate abnormal accumulation of neurofilament, in both their cell bodies and axons. To date, only a few approved treatments (e.g., mechanical ventilation and riluzole) prolong survival in ALS patients to some extent. However, the development of more effective neuroprotective therapies remains impeded by our limited knowledge of the actual mechanisms by which neurons die in ALS, and of how the disease progresses and propagates.
ALS, like other common neurodegenerative disorders, is sporadic in the vast majority of patients, and familial in only a few (1). The clinical and pathological expressions of ALS are almost indistinguishable between the familial and sporadic forms, although often in the former the age at onset is younger, the course of the disease more rapid, and the survival after diagnosis shorter (1). The cause of sporadic ALS remains unknown, while that of at least some familial forms has been identified (see below). Although the identified gene defects responsible for ALS account for a minute fraction of cases, most experts believe that unraveling the molecular basis by which those mutant gene products cause neurodegeneration may shed light on the etiopathogenesis of the common sporadic form of ALS.
TL;DR: Results indicate hyperphosphorylation of the retinoblastoma protein in motor neurons during ALS, concurrent with increased levels of cyclin D, and redistribution of E2F-1 into the cytoplasm of motor neurons and glia, and suggest that G 1 to S phase activation occurs during ALS and may participate in molecular mechanisms regulating motor neuron death.
Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of the motor neurons in the cerebral cortex, brain stem, and spinal cord. However, the mechanisms that regulate the initiation and/or progression of motor neuron loss in this disease remain enigmatic. Cell-cycle proteins and transcriptional regulators such as cyclins, cyclin-associated kinases, the retinoblastoma gene product (pRb), and E2F-1 function during cellular proliferation, differentiation, and cell death pathways. Recent data has implicated increased expression and activation of various cell-cycle proteins in neuronal cell death. We have examined the expression and subcellular distribution of G 1 to S phase cell-cycle regulators in the spinal cord, motor cortex, and sensory cortex from clinically and neuropathologically diagnosed sporadic ALS cases and age-matched controls. Our results indicate hyperphosphorylation of the retinoblastoma protein in motor neurons during ALS, concurrent with increased levels of cyclin D, and redistribution of E2F-1 into the cytoplasm of motor neurons and glia. These data suggest that G 1 to S phase activation occurs during ALS and may participate in molecular mechanisms regulating motor neuron death.
TL;DR: The experimental and human tissue‐based evidence for the involvement of such mechanisms in neuronal death associated with the motor system disorders of X‐linked spinobulbar muscular atrophy and amyotrophic lateral sclerosis is reviewed.
Abstract: Toxicity associated with abnormal protein folding and protein aggregation are major hypotheses for neurodegeneration. This article comparatively reviews the experimental and human tissue-based evidence for the involvement of such mechanisms in neuronal death associated with the motor system disorders of X-linked spinobulbar muscular atrophy (SBMA; Kennedy's disease) and amyotrophic lateral sclerosis (ALS), especially disease related to mutations in the superoxide dismutase (SOD1) gene. Evidence from transgenic mouse, Drosophila and cell culture models of SBMA, in common with other trinucleotide repeat expansion disorders, show protein aggregation of the mutated androgen receptor, and intraneuronal accumulation of aggregated protein, to be obligate mechanisms. Strong experimental data link these phenomena with downstream biochemical events involving gene transcription pathways (CREB-binding protein) and interactions with protein chaperone systems. Manipulations of these pathways are already established in experimental systems of trinucleotide repeat disorders as potential beneficial targets for therapeutic activity. In contrast, the evidence for the role of protein aggregation in models of SOD1-linked familial ALS is less clear-cut. Several classes of intraneuronal inclusion body have been described, some of which are invariably present. However, the lack of understanding of the biochemical basis of the most frequent inclusion in sporadic ALS, the ubiquitinated inclusion, has hampered research. The toxicity associated with expression of mutant SOD1 has been intensively studied however. Abnormal protein aggregation and folding is the only one of the four major hypotheses for the mechanism of neuronal degeneration in this disorder currently under investigation (the others comprise oxidative stress, axonal transport and cytoskeletal dysfunctions, and glutamatergic excitotoxicity). Whilst hyaline inclusions, which are strongly immunoreactive to SOD1, are linked to degeneration in SOD1 mutant mouse models, the evidence from human tissue is less consistent and convincing. A role for mutant SOD1 aggregation in the mitochondrial dysfunction associated with ALS, and in potentially toxic interactions with heat shock proteins, both leading to apoptosis, are supported by some experimental data. Direct in vitro data on mutant SOD1 show evidence for spontaneous oligomerization, but the role of such oligomers remains to be elucidated, and therapeutic strategies are less well developed for this familial variant of ALS.
TL;DR: This review presents a tentative classification of the “major” ALS genes and ALS “susceptibility” genes, that may act as susceptibility factors for neurodegeneration in interaction with other genetic or environmental risk factors.
Abstract: Amyotrophic lateral sclerosis (ALS) is a late onset, rapidly progressive and ultimately fatal neurological disorder, caused by the loss of motor neurons in the brain and spinal cord. Familial aggregation of ALS, with an age-dependent but high penetrance, is a major risk factor for ALS. Familial ALS (FALS) is clinically and genetically heterogeneous. Three genes and linkage to four additional gene loci have been identified so far and may either predominantly lead to ALS (ALSI-ALS6) or cause multisystem neurodegeneration with ALS as an occasional symptom (tauopathies, ALS-dementia complex). This review presents a tentative classification of the "major" ALS genes and ALS "susceptibility" genes, that may act as susceptibility factors for neurodegeneration in interaction with other genetic or environmental risk factors. Considering that mutations in ALS genes explain approximately 10% of familial as well as sporadic ALS, and most remaining cases of the discase are thought to result form the interaction of several genes and environmental factors, ALS is a paradigm for multifactorial discases.
TL;DR: A genetic linkage screen in 16 pedigrees with FALS with no evidence for mutations in the SOD1 gene is performed and novel ALS loci on chromosomes 16 and 20 are identified and will delineate pathways implicated as determinants of motor-neuron viability and provide insights into possible therapies for ALS.
Abstract: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, adult-onset motor neuron disease that arises as a dominantly inherited trait in ∼10% of ALS cases. Mutations in one gene, cytosolic Cu/Zn superoxide dismutase (SOD1), account for ∼25% of familial ALS (FALS) cases. We have performed a genetic linkage screen in 16 pedigrees with FALS with no evidence for mutations in the SOD1 gene and have identified novel ALS loci on chromosomes 16 and 20. The analysis of these genes will delineate pathways implicated as determinants of motor-neuron viability and provide insights into possible therapies for ALS.
TL;DR: It is concluded that riluzole therapy improves ALS survival in everyday clinical practice by a short period of time and stopping the medication in advanced ALS should be reconsidered.
Abstract: Riluzole is the only therapy proven in clinical trials to prolong amyotrophic lateral sclerosis (ALS) survival (approximately three months) Questions remain concerning riluzole's effectiveness in everyday practice, the appropriate duration of treatment, which certain subtypes of ALS specifically benefit from the medication, and whether early administration prolongs survival in ALS patients We report the results of a population-based outcome study of riluzole in the Irish ALS population over a five-year period Using data from the Irish ALS Register, we examined the survival of patients diagnosed with ALS between 1 January 1996 and 31 December 2000 who attended a general neurology clinic (n = 264 patients, MD = 16) An intention to treat analysis is employed 149 (61 %) patients were prescribed riluzole and the remaining 99 (39 %) were not Riluzole therapy reduced mortality rate by 23 % and 15 % at 6 and 12 months respectively and prolonged survival by approximately four months This beneficial effect was lost in prolonged follow-up Suspected or possible ALS patients receiving riluzole experienced similar improvement in survival as the overall cohort Survival benefit was more marked among patients with bulbar-onset disease Multivariate analysis did not show riluzole to be an independent predictor of survival We conclude that riluzole therapy improves ALS survival in everyday clinical practice by a short period of time This beneficial effect is transient and stopping the medication in advanced ALS should be reconsidered Bulbar-onset patients appear to particularly benefit from riluzole for unclear reasons Our initial observations support riluzole use in early ALS
TL;DR: This study provides the first experimental evidence that prophylactic treatment with COX‐2 inhibitors can significantly delay the onset of motor dysfunction in the SOD1‐G93A transgenic mouse model of ALS.
Abstract: Recent studies indicate that the proinflammatory enzyme cyclooxygenase (COX)-2, an enzyme involved in inflammatory cascades but also normal neuronal activities, is elevated in the brain and spinal cord of amyotrophic lateral sclerosis (ALS) patients and ALS mouse model systems. On the basis of this evidence, we explored the impact of COX-2 inhibition on the onset and progression of ALS-like disease in the G93A human superoxide dismutase (SOD)1 mouse model of ALS. We found that prophylactic administration of nimesulide, a preferential COX-2 inhibitor, in the feed resulted in a significant delay in the onset of ALS type motor impairment. This delay of ALS symptomatology temporally overlapped with the inhibition of prostaglandin E2 elevation in the spinal cord of SOD1-G93A transgenic mice relative to untreated SOD1-G93A controls. This study strongly supports a role for COX-2 in the pathophysiology of ALS and provides the first experimental evidence that prophylactic treatment with COX-2 inhibitors can significantly delay the onset of motor dysfunction in the SOD1-G93A transgenic mouse model of ALS.
TL;DR: It is found that glutamate induces far greater reactive oxygen species (ROS) generation in cultured motor neurons than in other spinal neurons, and the ROS seem to be able to leave the motor neurons and induce oxidation and disruption of glutamate uptake in neighboring astrocytes.
Abstract: Observations of elevated CSF glutamate in amyotrophic lateral sclerosis (ALS), together with findings that motor neurons are selectively vulnerable to glutamate receptor-mediated ("excitotoxic") injury, support an excitotoxic contribution to the motor neuron loss in the disease. However, the basis of the apparent loss of astrocytic glutamate transport capacity in affected areas of motor cortex and spinal cord, which probably underlies the extracellular glutamate elevations, is unexplained. Here, we find that glutamate induces far greater reactive oxygen species (ROS) generation in cultured motor neurons than in other spinal neurons. In addition, we found that the ROS seem to be able to leave the motor neurons and induce oxidation and disruption of glutamate uptake in neighboring astrocytes. Correspondingly, in a transgenic mouse model of ALS, protein oxidation was increased in regions immediately surrounding motor neurons. These results provide a mechanism that can account for the localized loss of glial glutamate transport seen in the disease. Furthermore, the observations lend support for a feedforward model involving reciprocal interactions between motor neurons and glia, which may prove useful in understanding ALS pathogenesis.
TL;DR: Results indicate that a combination approach consisting of three drugs for distinct targets in the complex pathway to neuronal death, minocycline, riluzole, and nimodipine may represent an effective strategy for ALS treatment.
Abstract: There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). Because evidence suggests that multiple pathways may contribute to ALS pathogenesis, we tested in a mouse model of ALS (SOD1(G37R) mice) a combination approach consisting of three drugs for distinct targets in the complex pathway to neuronal death: minocycline, an antimicrobial agent that inhibits microglial activation, riluzole, a glutamate antagonist, and nimodipine, a voltage-gated calcium channel blocker. The efficacy of this three-drug cocktail was remarkable when administered in the diet from late presymptomatic stage (8-9 months). It delayed the onset of disease, slowed the loss of muscle strength, and increased the average longevity of SOD1(G37R) mice by 6 weeks. The protective effect of the treatment was corroborated by the reduced immunodetection signals for markers of gliosis and neurodegeneration in the spinal cord of SOD1(G37R) mice. These results indicate that such three-drug combination may represent an effective strategy for ALS treatment.
TL;DR: Results suggest that an altered motor neuron excitability accompanies an ALS associated mutation and that may contribute to the pathogenesis of the disease.
TL;DR: Significant advances in both symptomatic and adjunctive therapy have resulted in prolonged quality and duration of life and the suggestion that multiple distinct etiologies may be responsible is suggested.
Abstract: Amyotrophic lateral sclerosis (ALS), once thought to be a rare neurodegenerative disease, affects between 1.2 and 1.8/100,000 individuals. This age‐dependent disorder, similar to other major neurological disorders of the aging population (Alzheimer's and Parkinson's disease) is increasing in incidence at a rate which cannot be accounted for by population aging alone. Multiple clinical variants of ALS are now recognized which are associated with a spectrum of clinical outcomes from aggressive to rather indolent. Three variants of ALS are generally accepted, including the western Pacific type (often associated with dementia), familial (the majority of which are autosomal dominant in their inheritance) and classic sporadic ALS. Considerable biological heterogeneity underlies the disease process of ALS. By the time ALS is clinically evident, derangements at the cellular level in ALS are extensive and include alterations in the cytoskeleton, mitochondrial function, microglial activation, and the metabolism of ...
TL;DR: Dropped head syndrome is an important clinical sign and usually occurs as an early feature within the first one to two years after the onset of ALS.
Abstract: Background: “Dropped head syndrome” caused by neck extensor weakness has been reported in a variety of neuromuscular disorders. Previously published reports include isolated cases with amyotrophic lateral sclerosis (ALS). In this report, nine patients with ALS and dropped head syndrome seen during a 20 year period are described. Patients and investigations: Between 1981 and 2000, 683 patients with ALS were diagnosed, based on El Escorial criteria. Nine of these had profound neck extensor weakness observed as an early feature, or developing during the later stages of the disease. The protocol for evaluation included detailed clinical history, neurological examination, electromyography, and nerve conduction studies. Investigations were undertaken to exclude malignancy, lymphoproliferative disorders, thyroid dysfunction, and collagen vascular disease. Results: The incidence of dropped head syndrome was 1.3%. The mean (SD) age of the affected patients was 53.3 (10.3) years (range 33 to 65), with an equal distribution of cases in the fourth to seventh decades. In six patients, head drop was an early feature (mean interval from onset of illness 11.6 months (range 3 to 24)); in three it was late (between three and eight years after onset). In five patients, mild neck flexor weakness was present in addition to severe extensor weakness. In all nine patients there were diffuse upper and lower motor neurone signs. None of the patients had difficulty in breathing but all had difficulty in swallowing and social embarrassment, both of which could be corrected by simple measures. Conclusions: Dropped head syndrome is an important clinical sign and usually occurs as an early feature within the first one to two years after the onset of ALS. The cause of dropped head syndrome in these nine cases could be easily established as ALS by the presence of generalised signs.