Showing papers on "Amyotrophic lateral sclerosis published in 1999"
TL;DR: Reduced transport of selective cargoes of slow transport, especially tubulin, arises months before neurodegeneration in two SOD1 mutations linked to familial ALS, verifying the hypothesis that damage to the cargoe or machinery ofslow transport is an early feature of toxicity mediated by mutant SOD 1.
Abstract: Mutations in copper/zinc superoxide dismutase 1 (SOD1), primary causes of human amyotrophic lateral sclerosis (ALS), provoke motor neuron death through an unidentified toxic property. The known neurofilament-dependent slowing of axonal transport, combined with the prominent misaccumulation of neurofilaments in ALS, suggests that an important aspect of toxicity may arise from damage to transport. Here we verify this hypothesis for two SOD1 mutations linked to familial ALS. Reduced transport of selective cargoes of slow transport, especially tubulin, arises months before neurodegeneration. For one mutant, this represents the earliest detectable abnormality. Thus, damage to the cargoes or machinery of slow transport is an early feature of toxicity mediated by mutant SOD1.
600 citations
TL;DR: Zinc-deficient SOD may participate in both sporadic and familial ALS by an oxidative mechanism involving nitric oxide, and when replete with zinc, neither ALS-mutant nor wild-type copper, zinc SODs were toxic, and both protected motor neurons from trophic factor withdrawal.
Abstract: Mutations in copper, zinc superoxide dismutase (SOD) have been implicated in the selective death of motor neurons in 2 percent of amyotrophic lateral sclerosis (ALS) patients. The loss of zinc from either wild-type or ALS-mutant SODs was sufficient to induce apoptosis in cultured motor neurons. Toxicity required that copper be bound to SOD and depended on endogenous production of nitric oxide. When replete with zinc, neither ALS-mutant nor wild-type copper, zinc SODs were toxic, and both protected motor neurons from trophic factor withdrawal. Thus, zinc-deficient SOD may participate in both sporadic and familial ALS by an oxidative mechanism involving nitric oxide.
578 citations
TL;DR: Inclusions in tau-immunoreactive filaments were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules (MTs), and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness.
573 citations
TL;DR: It is concluded that a PCD mechanism, involving cytosol-to-membrane and membrane- to-cytosol redistribution of cell death proteins and caspase-3 activation, participates in the pathogenesis of ALS.
Abstract: The mechanisms for neurodegeneration in amyotrophic lateral sclerosis (ALS) are not understood. We found that motor neuron degeneration in ALS structurally resembles apoptosis. The progression of neuronal death is divisible into 3 sequential stages: chromatolysis, somatodendritic attrition, and apoptosis. In ALS spinal cord anterior horn and motor cortex, DNA fragmentation is detectable in situ and in gels and is internucleosomal, occurring in the presence of DNA fragmentation factor-45/40 activation and increased caspase-3 activity. By immunoblotting, changes occur in the subcellular distribution of cell death proteins that would promote apoptosis. In selectively vulnerable CNS regions in ALS compared with controls, the proapoptotic proteins Bax and Bak are elevated in the mitochondrial-enriched membrane compartment, but are reduced or unchanged in the cytosol. In contrast, the antiapoptotic protein Bcl-2 is decreased in the mitochondrial-enriched membrane compartment of vulnerable regions in ALS, but is increased in the cytosol, whereas Bcl-xL levels are unchanged in both subcellular compartments. Coimmunoprecipitation experiments showed that Bax-Bax interactions are greater in the mitochondrial-enriched membrane compartment of ALS motor cortex compared with controls, whereas Bax-Bcl-2 interactions are lower in the membrane compartment of ALS motor cortex compared with controls. We conclude that a PCD mechanism, involving cytosol-to-membrane and membrane-to-cytosol redistribution of cell death proteins and caspase-3 activation, participates in the pathogenesis of ALS.
356 citations
TL;DR: There is a selective decrease in the activity of the mitochondrial DNA–encoded enzyme cytochrome c oxidase in human spinal cord motor neurons in sporadic ALS, and this may not only be important in neuronal cell death but could well be caused by oxidative damage to mitochondrial DNA leading to the accumulation of mitochondrial DNA mutations.
Abstract: The mechanism of selective loss of motor neurons in amyotrophic lateral sclerosis (ALS) has not been clarified. Mitochondrial pathology is present in central nervous system tissue from ALS cases and occurs as an early event in a mouse model of ALS. We demonstrate that, in sporadic ALS, there is a selective decrease in the activity of the mitochondrial DNA-encoded enzyme cytochrome c oxidase in human spinal cord motor neurons. We propose that this may not only be important in neuronal cell death but could well be caused by oxidative damage to mitochondrial DNA leading to the accumulation of mitochondrial DNA mutations.
324 citations
TL;DR: Evidence is presented that mutations in the Cu/Zn‐superoxidedismutase (SOD‐1) gene underlie some familial cases of amytotrophic lateral sclerosis, a neurodegenerative disorder charactreized by loss of cortical, brainstem, and spinal motor nrurons, and that insufficiency of molecular chaperones may be directly involved in loss of motor neurons in this disease.
Abstract: Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene underlie some familial cases of amyotrophic lateral sclerosis, a neurodegenerative disorder characterized by loss of cortical, brainstem, and spinal motor neurons. We present evidence that SOD-1 mutants alter the activity of molecular chaperones that aid in proper protein folding and targeting of abnormal proteins for degradation. In a cultured cell line (NIH 3T3), resistance to mutant SOD-1 toxicity correlated with increased overall chaperoning activity (measured by the ability of cytosolic extracts to prevent heat denaturation of catalase) as well as with up-regulation of individual chaperones/stress proteins. In transgenic mice expressing human SOD-1 with the G93A mutation, chaperoning activity was decreased in lumbar spinal cord but increased or unchanged in clinically unaffected tissues. Increasing the level of the stress-inducible chaperone 70-kDa heat shock protein by gene transfer reduced formation of mutant SOD-containing proteinaceous aggregates in cultured primary motor neurons expressing G93A SOD-1 and prolonged their survival. We propose that insufficiency of molecular chaperones may be directly involved in loss of motor neurons in this disease.
270 citations
TL;DR: It is reported here that sustained overexpression of wild-type peripherin in mice provokes massive and selective degeneration of motor axons during aging, and IF inclusions containing peripherin may play a contributory role in motor neuron disease.
Abstract: Peripherin, a type III intermediate filament (IF) protein, upregulated by injury and inflammatory cytokines, is a component of IF inclusion bodies associated with degenerating motor neurons in sporadic amyotrophic lateral sclerosis (ALS). We report here that sustained overexpression of wild-type peripherin in mice provokes massive and selective degeneration of motor axons during aging. Remarkably, the onset of peripherin-mediated disease was precipitated by a deficiency of neurofilament light (NF-L) protein, a phenomenon associated with sporadic ALS. In NF-L null mice, the overexpression of peripherin led to early- onset formation of IF inclusions and to the selective death of spinal motor neurons at 6 mo of age. We also report the formation of similar peripherin inclusions in presymptomatic transgenic mice expressing a mutant form of superoxide dismutase linked to ALS. Taken together, these results suggest that IF inclusions containing peripherin may play a contributory role in motor neuron disease.
251 citations
TL;DR: The physiologic abnormalities in mFALS mice resemble those in human ALS and SOD1-deficient mice exhibit a qualitatively different pattern of motor unit remodeling that suggests that axonal sprouting and reinnervation of denervated muscle fibers are functionally impaired in the absence of S OD1.
Abstract: Objective: To characterize the motor neuron dysfunction in two models by performing physiologic and morphometric studies. Background: Mutations in the gene encoding cytosolic superoxide dismutase 1 (SOD1) account for 25% of familial ALS (FALS). Transgenes with these mutations produce a pattern of lower motor neuron degeneration similar to that seen in patients with FALS. In contrast, mice lacking SOD1 develop subtle motor symptoms by approximately 6 months of age. Methods: Physiologic measurements, including motor conduction and motor unit estimation, were analyzed in normal mice, mice bearing the human transgene for FALS (mFALS mice), and knockout mice deficient in SOD1 (SOD1-KO). In addition, morphometric analysis was performed on the spinal cords of SOD1-KO and normal mice. Results: In mFALS mice, the motor unit number in the distal hind limb declined before behavioral abnormalities appeared, and motor unit size increased. Compound motor action potential amplitude and distal motor latency remained normal until later in the disease. In SOD1-KO mice, motor unit numbers were reduced early but declined slowly with age. In contrast with the mFALS mice, SOD1-KO mice demonstrated only a modest increase in motor unit size. Morphometric analysis of the spinal cords from normal and SOD1-KO mice showed no significant differences in the number and size of motor neurons. Conclusions: The physiologic abnormalities in mFALS mice resemble those in human ALS. SOD1-deficient mice exhibit a qualitatively different pattern of motor unit remodeling that suggests that axonal sprouting and reinnervation of denervated muscle fibers are functionally impaired in the absence of SOD1.
196 citations
TL;DR: The decrement of GluR2 mRNA editing efficiency is unique to the ventral gray of ALS cases and may be closely linked to the etiology of ALS.
Abstract: Enhancement of calcium influx through the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptor is a plausible mechanism underlying selective neuronal death in amyotrophic lateral sclerosis (ALS). The calcium conductance of the AMPA receptor is regulated by the GluR2 subunit that is edited at the glutamine/arginine residue site in the subunit assembly. We investigated the molecular changes of GluR2 mRNA in the spinal cord of ALS cases, those of cases with other neurological diseases, and those of normal cases using reverse transcription-polymerase chain reaction combined with restriction enzyme cleavage. We found that the editing efficiency was significantly lower only in the ventral gray of ALS cases (virtually 0% in 2 cases) than in any spinal region of the disease controls and normal controls. In addition, expression of GluR2 mRNA is lower in the ventral gray of the ALS cases and disease controls than in that of the normal controls. The above molecular changes of GluR2 mRNA in the ventral gray of ALS cases may enhance calcium influx through AMPA receptors, thereby promoting neuronal vulnerability. The decrement of GluR2 mRNA editing efficiency is unique to the ventral gray of ALS cases and may be closely linked to the etiology of ALS.
192 citations
TL;DR: It is concluded that the retrograde death of motor neurons in the adult spinal cord after sciatic nerve avulsion is apoptosis, and accumulation of active mitochondria within the perikaryon and oxidative damage to nucleic acids and proteins may contribute to the mechanisms for apoptosis.
Abstract: The mechanisms for motor neuron degeneration and regeneration in adult spinal cord following axotomy and target deprivation are not fully understood. We used a unilateral sciatic nerve avulsion model in adult rats to test the hypothesis that retrograde degeneration of motor neurons resembles apoptosis. By 21 days postlesion, the number of large motor neurons in lumbar spinal cord was reduced by ∼30%. The death of motor neurons was confirmed using the terminal transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling method for detecting fragmentation of nuclear DNA. Motor neuron degeneration was characterized by aberrant accumulation of perikaryal phosphorylated neurofilaments. Structurally, motor neuron death was apoptosis. Apoptotic motor neurons undergo chromatolysis followed by progressive cytoplasmic and nuclear condensation with chromatin compaction into uniformly large round clumps. Prior to apoptosis, functionally active mitochondria accumulate within chromatolytic motor neurons, as determined by cytochrome c oxidase activity. These dying motor neurons sustain oxidative damage to proteins and nucleic acids within the first 7 days after injury during the progression of apoptosis, as identified by immunodetection of nitrotyrosine and hydroxyl-modified deoxyguanosine and guanosine. We conclude that the retrograde death of motor neurons in the adult spinal cord after sciatic nerve avulsion is apoptosis. Accumulation of active mitochondria within the perikaryon and oxidative damage to nucleic acids and proteins may contribute to the mechanisms for apoptosis of motor neurons in the adult spinal cord. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 185–201, 1999
163 citations
TL;DR: Results show a close temporal correlation between the onset of neuronal degeneration and the beginning of astrogliosis in this neurodegenerative disease and reveal a novel spatial relationship that is consistent with the view that astrocytes play an active role in the neuronal degenerations process.
Abstract: Astrocytic proliferation and hypertrophy (astrogliosis) are associated with neuronal injury. However, neither the temporal nor the spatial relationship between astrocytes and injured neurons is clear, especially in neurodegenerative diseases. We investigated these questions in a mouse amyotrophic lateral sclerosis (ALS) model. The initial increase in astrogliosis coincided with the onset of clinical disease and massive mitochondrial vacuolation in motor neurons. After disease onset, astrogliosis increased further in parallel with the number of degenerating motor neurons. Examination of individual astrocytes by three-dimensional reconstruction revealed that astrocytes extended their processes toward, wrapped around, and sometimes penetrated vacuoles derived from neuronal mitochondria. These results show a close temporal correlation between the onset of neuronal degeneration and the beginning of astrogliosis in this neurodegenerative disease and reveal a novel spatial relationship that is consistent with the view that astrocytes play an active role in the neuronal degeneration process.
TL;DR: The results indicate that the involvement of EAAT2 transcripts in ALS is unlikely to be primary, and more complex than previously recognized.
TL;DR: The data suggest that genistein has both estrogen-dependent and estrogen-independent neuroprotective activities and it should be investigated as a prophylactic agent against pathologic conditions such as ALS and stroke.
TL;DR: Results provide direct evidence that the SOD1 mutation leads to impaired fast axonal transport, particularly in the anterograde direction at an early, asymptomatic stage preceding loss of spinal motor neurons and peripheral axons in transgenic mice implicated for human FALS.
TL;DR: Patients presenting with severe weakness that is fully isolated to the upper limbs, without pyramidal signs, may have a relatively stable variant of motor neuron disease.
Abstract: Objective: To describe a sporadic motor neuron disorder that remains largely restricted to the upper limbs over time. Background: Progressive amyotrophy that is isolated to the upper limbs in an adult often suggests ALS. The fact that weakness can remain largely confined to the arms for long periods of time in individuals presenting with this phenotype has not been emphasized. Methods: We reviewed the records of patients who had a neurogenic “man-in-the-barrel” phenotype documented by examination at least 18 months after onset. These patients had severe bilateral upper-extremity neurogenic atrophy that spared lower-extremity, respiratory, and bulbar musculature. Results: Nine of 10 patients meeting these criteria had a purely lower motor neuron disorder. During follow-up periods ranging from 3 to 11 years from onset, only three patients developed lower-extremity weakness, and none developed respiratory or bulbar dysfunction or lost the ability to ambulate. Conclusion: Patients presenting with severe weakness that is fully isolated to the upper limbs, without pyramidal signs, may have a relatively stable variant of motor neuron disease.
TL;DR: The clinical and electrodiagnostic findings in 49 affected family members and neuropathological findings from two autopsies of a Maryland kindred with autosomal dominant juvenile ALS linked to the chromosome 9q34 region (ALS4) are reported, extending the clinical, pathological and genetic heterogeneity of familial ALS and juvenile ALS.
Abstract: Juvenile amyotrophic lateral sclerosis (ALS) is a form of chronic motor neuron disease characterized by combined upper and lower motor neuron symptoms and signs with onset prior to age 25 years. We report the clinical and electrodiagnostic findings in 49 affected family members and neuropathological findings from two autopsies of a Maryland kindred with autosomal dominant juvenile ALS linked to the chromosome 9q34 region (ALS4). Patients ranged in age from 12 to 85 years (mean 45 years) and the mean age of onset was 17 years. Distal weakness and atrophy was associated with pyramidal signs (43/49) and normal sensation (44/49). Motor conduction studies (n = 8) showed reduced evoked amplitudes and normal conduction parameters. Sensory conduction studies (n = 8), quantitative sensory testing (n = 4) and intracutaneous sensory fibres in skin biopsies (n = 6) were normal in all patients tested. Electromyography showed distal more than proximal chronic partial denervation and reinnervation (n = 8). Post-mortem spinal cord tissue demonstrated atrophic spinal cords with marked loss of anterior horn cells and degeneration of corticospinal tracts, as well as loss of neurons in the dorsal root ganglia and degeneration of the posterior columns. Axonal spheroids were present in the grey matter of the spinal cord, the dorsal root entry zones and the peripheral nerves. Motor and sensory roots, as well as peripheral nerves, showed significant axonal loss. Swellings were prominent around motor neurons, probably representing changes in presynaptic terminals. These studies define autosomal dominant juvenile ALS linked to the chromosome 9q34 region (ALS4) and extend the clinical, pathological and genetic heterogeneity of familial ALS and juvenile ALS.
TL;DR: The relationship between amyotrophic lateral sclerosis and cigarette smoking in a case-control study conducted in New England from 1993 to 1996 was explored, and the weak relationship of ALS with alcohol use was apparently due to confounding by smoking.
Abstract: We explored the relationship between amyotrophic lateral sclerosis (ALS) and cigarette smoking in a case-control study conducted in New England from 1993 to 1996. Recently diagnosed ALS cases (n = 109
TL;DR: Until a definitive treatment or cure for ALS is found, the multifaceted rehabilitation team approach remains the best hope for improving health and survival in this devastating illness.
TL;DR: It is concluded that a dietary manipulation known to extend lifespan has no beneficial effect in an animal model of familial ALS.
TL;DR: Multi-parameter respiratory monitoring during sleep should be included in the routine evaluation of ALS patients at an early clinical stage, especially those with predominantly bulbar involvement, in order to predict early respiratory failure.
TL;DR: It is suggested that the antioxidant properties of aspirin are responsible for the positive effects in this model and support the use of antioxidants as effective therapy for ALS.
TL;DR: In this paper, the authors investigated the possibility of reducing motor decline by exercising these patients to the anaerobic threshold, but simultaneously compensating the respiratory insufficiency with the Bipap STD.
TL;DR: In this paper, the authors have shown that the disease may be multidegenerative, with oculomotor or cerebellar involvement, and the detailed description of the Scandinavian D90A homozygous mutation is very informative in this regard.
TL;DR: The more severe involvement of the APB probably reflects the specific pathophysiology in ALS, and possible mechanisms for the dissociated involvement are discussed.
Abstract: In some patients with amyotrophic lateral sclerosis (ALS), the thenar hand is more severely affected than the hypothenar hand. To quantify the dissociated involvement, we examined the motor unit number estimate (MUNE) of both the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles in 23 patients with ALS. Whereas ALS patients had significantly smaller MUNEs than normal subjects in both muscles, the extent of motor unit loss was significantly greater in the APB than ADM. Moreover, a simple comparison of the amplitude of compound muscle action potentials (CMAPs) showed that ALS patients had significantly smaller APB/ADM ratios than normal subjects and patients with cervical spondylotic amyotrophy, bulbospinal muscular atrophy, or peripheral neuropathy. The more severe involvement of the APB probably reflects the specific pathophysiology in ALS, and possible mechanisms for the dissociated involvement are discussed.
TL;DR: This review will present the important findings from transgenic mice and culture models, provide a framework in which to evaluate these findings, and speculate on the mechanism of degeneration initiated by the mutations in SOD-1.
Journal Article•
TL;DR: Amyotrophic lateral sclerosis, commonly called Lou Gehrig's disease, is a progressive neuromuscular condition characterized by weakness, muscle wasting, fasciculations and increased reflexes.
Abstract: Amyotrophic lateral sclerosis (ALS), commonly called Lou Gehrig's disease, is a progressive neuromuscular condition characterized by weakness, muscle wasting, fasciculations and increased reflexes. Approximately 30,000 Americans currently have the disease. The annual incidence rate is one to two cases per 100,000. The disease is most commonly diagnosed in middle age and affects more men than women. It usually presents with problems in dexterity or gait resulting from muscle weakness. Difficulty in speaking or swallowing is the initial symptom in the bulbar form of the disease. Over a period of months or years, patients with ALS develop severe, progressive muscular weakness and other symptoms caused by loss of function in both upper and lower motor neurons. Sphincter control, sensory function, intellectual abilities and skin integrity are preserved. Patients become completely disabled, often requiring ventilatory support and gastrostomy. Death usually occurs within five years of diagnosis and is attributed to respiratory failure or cachexia. The etiology of the disease is unknown. Current research is focused on abnormalities of neuronal cell metabolism involving glutamate and the role of potential neurotoxins and neurotrophic factors. New drugs are being developed based on these theories. Current management involves aggressive, individualized alleviation of symptoms and complications.
TL;DR: This population-based case-control study was conducted in three counties in western Washington state between 1990 and 1994 to assess the association between amyotrophic lateral sclerosis (ALS) and several hypothesized risk factors, including a family history of neurodegenerative diseases, physical trauma, rural residence, travel, and medical history.
Abstract: This population-based case-control study was conducted in three counties in western Washington state (USA) between 1990 and 1994 to assess the association between amyotrophic lateral sclerosis (ALS) a
TL;DR: Trientine and ascorbate, known to have a beneficial effect in an animal model of Wilson disease, were administered to transgenic mice overexpressing a mutated human SOD1 (G93A) and the onset of neurological signs in the treated group was significantly delayed compared with that in the control group.
TL;DR: It is found striking that these particular neurons are those which are vulnerable to neurodegeneration in diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).
TL;DR: Clinically, backward falls and retropulsion may occur early in ALS, and necropsy studies performed late in the course of ALS have shown degeneration in extrapyramidal sites—for example, the globus pallidus, thalamus, and substantia nigra.
Abstract: Three patients with sporadic amyotrophic lateral sclerosis (ALS) presented with a history of backward falls. Impaired postural reflexes and retropulsion accompanied clinical features of ALS. Hypokinesia, decreased arm swing, and a positive glabellar tap were noted in two of these three patients. Cognitive impairment, tremor, axial rigidity, sphincter dysfunction, nuchal dystonia, dysautonomia, and oculomotor dysfunction were absent. Brain MRI disclosed bilateral T2 weighted hyperintensities in the internal capsule and globus pallidus in one patient. Necropsy studies performed late in the course of ALS have shown degeneration in extrapyramidal sites—for example, the globus pallidus, thalamus, and substantia nigra. Clinically, backward falls and retropulsion may occur early in ALS. This may reflect extrapyramidal involvement.