Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the intracellular metalloenzyme superoxide dismutase 1 (SOD1) are linked to neurotoxicity in familial amyotrophic lateral sclerosis (ALS) by an unclear mechanism. Golgi fragmentation and endoplasmic reticulum stress are early hallmarks of spinal motor neuron pathology in transgenic mice overexpressing mutant SOD1, suggesting that dysfunction of the neuronal secretory pathway may contribute to ALS pathogenesis. We therefore proposed that mutant SOD1 directly engages and modulates the secretory pathway based on recent evidence of SOD1 secretion in diverse human cell lines. Here, we demonstrate that a fraction of active endogenous SOD1 is secreted by NSC-34 motor neuron-like cells via a brefeldin-A (BFA)-sensitive pathway. Expression of enhanced green fluorescent protein-tagged mutant human SOD1 (hSOD1-EGFP) in NSC-34 cells induced frequent cytoplasmic inclusions and protein insolubility that correlated with toxicity. In contrast, transfection of non-neuronal COS-7 cells resulted in mutant hSOD1-EGFP cytoplasmic inclusions, oligomerization, and fragmentation without detectable toxicity. Importantly, impaired secretion of hSOD1-EGFP was common to all 10 SOD1 mutants tested relative to wild-type protein in NSC-34 cells. Treatment with BFA inhibited hSOD1-EGFP secretion with pronounced BFA-induced toxicity in mutant cells. Extracellular targeting of mutant hSOD1-EGFP via SOD3 signal peptide fusion attenuated cytoplasmic inclusion formation and toxicity. The effect of elevated extracellular SOD1 was then evaluated in a transgenic rat model of ALS. Chronic intraspinal infusion of exogenous wild-type hSOD1 significantly delayed disease progression and endpoint in transgenic SOD1(G93A) rats. Collectively, these results suggest novel extracellular roles for SOD1 in ALS and support a causal relationship between mutant SOD1 secretion and intraneuronal toxicity.
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PMID:Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis. 1563 72

A "gain-of-function" toxic property of mutant Cu-Zn superoxide dismutase 1 (SOD1) is involved in the pathogenesis of some familial cases of amyotrophic lateral sclerosis (ALS). Expression of a mutant form of the human SOD1 gene in mice causes a degeneration of motor neurons, leading to progressive muscle weakness and hindlimb paralysis. Transgenic mice overexpressing a mutant human SOD1 gene (G93A-SOD1) were used to examine the mitochondrial involvement in familial ALS. We observed a decrease in mitochondrial respiration in brain and spinal cord of the G93A-SOD1 mice. This decrease was significant only at the last step of the respiratory chain (complex IV), and it was not observed in transgenic wild-type SOD1 and nontransgenic mice. Interestingly, this decrease was evident even at a very early age in mice, long before any clinical symptoms arose. The effect seemed to be CNS specific, because no decrease was observed in liver mitochondria. Differences in complex IV respiration between brain mitochondria of G93A-SOD1 and control mice were abolished when reduced cytochrome c was used as an electron donor, pinpointing the defect to cytochrome c. Submitochondrial studies showed that cytochrome c in the brain of G93A-SOD1 mice had a reduced association with the inner mitochondrial membrane (IMM). Brain mitochondrial lipids, including cardiolipin, had increased peroxidation in G93A-SOD1 mice. These results suggest a mechanism by which mutant SOD1 can disrupt the association of cytochrome c with the IMM, thereby priming an apoptotic program.
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PMID:Cytochrome c association with the inner mitochondrial membrane is impaired in the CNS of G93A-SOD1 mice. 1563 78

Mutations in the enzyme superoxide dismutase 1 (SOD1) initiate a progressive motoneurone degeneration in amyotrophic lateral sclerosis (ALS). Transgenic mice overexpressing this mutation develop a similar progressive motoneurone degeneration. In spinal motoneurones cultured from presymptomatic mice expressing the glycine to alanine mutation at base pair 93 (G93A) SOD1 mutation, a marked increase in the persistent component of the Na(+) current was observed, without changes in passive properties. This increase only enhanced neuronal excitability in high input conductance cells, as low input conductance cells exhibited a compensatory outward shift in the current remaining after Na(+) blockade. High input conductance motoneurones tend to be large, so these results may explain the tendency of large motoneurones to degenerate first in ALS. Riluzole, at the therapeutic concentration used to treat ALS, decreased neuronal excitability and persistent Na(+) current in G93A motoneurones to levels observed in the control motoneurones. Aberrations in the intrinsic electrical properties may be among the first symptoms to emerge in SOD1-linked ALS.
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PMID:Increased persistent Na(+) current and its effect on excitability in motoneurones cultured from mutant SOD1 mice. 1564 79

Oxidative stress is implicated in both the deposition and pathogenesis of beta-amyloid (Abeta) protein in Alzheimer's disease (AD). Accordingly, overexpression of the antioxidant enzyme superoxide dismutase 1 (SOD1) in neuronal cells and transgenic AD mice reduces Abeta toxicity and accumulation. In contrast, mutations in SOD1 associated with amyotrophic lateral sclerosis (ALS) confer enhanced pro-oxidative enzyme activities. We therefore examined whether ALS-linked mutant SOD1 overexpression in motor neuronal cells or transgenic ALS mice modulates Abeta toxicity or its accumulation in the brain. Aggregated, but not freshly solubilised, substrate-bound Abeta peptides induced degenerative morphology and cytotoxicity in motor neuron-like NSC-34 cells. Transfection of NSC-34 cells with human wild-type SOD1 attenuated Abeta-induced toxicity, however this neuroprotective effect was also observed for ALS-linked mutant SOD1. Analysis of the cerebral cortex, brainstem, cerebellum and olfactory bulb from transgenic SOD1G93A mice using enzyme-linked immunosorbent assay of acid-guanidine extracts revealed age-dependent elevations in Abeta levels, although not significantly different from wild-type mouse brain. In addition, brain amyloid protein precursor (APP) levels remained unaltered as a consequence of mutant SOD1 expression. We therefore conclude that mutant SOD1 overexpression promotes neither Abeta toxicity nor brain accumulation in these ALS models.
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PMID:Brain beta-amyloid accumulation in transgenic mice expressing mutant superoxide dismutase 1. 1567 51

An increasing body of evidence suggests that mitochondrial dysfunction plays an important role in the pathogenesis of familial amyotrophic lateral sclerosis associated with "gain of function" mutations in Cu/Zn superoxide dismutase 1 (SOD1). SOD1 is mostly a cytosolic protein, but a portion of SOD1 is localized in mitochondria of patients with familial amyotrophic lateral sclerosis and transgenic mouse models of the disease. Despite the finding that mutant SOD1 localizes in mitochondria, the pathogenic significance of the mitochondrial mutant SOD1 remains to be elucidated. Here, we demonstrate that both wild-type and mutant human SOD1 accumulate in brain mitochondria of transgenic mice and that SOD1 displays a very complex intramitochondrial compartmentalization. For the first time, we show that, in addition to being in the mitochondrial outer membrane and intermembrane space, SOD1 is also localized in the mitochondrial matrix. Importantly, we show that aberrant SOD1 macromolecular aggregates are formed in the matrix of brain mitochondria. This suggests that mutant SOD1 in the brain mitochondrial matrix is misfolded and prone to aggregation, which may contribute to selective neuronal degeneration.
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PMID:Mutant superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice. 1575 54

Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system in middle and old age that leads to progressive loss of spinal motoneurons. Transgenic mice overexpressing mutated human Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) reproduce clinical features of the familial form of ALS. However, changes in SOD1 activity do not correlate with severity of motor decline in sporadic cases, indicating that targets unrelated to superoxide metabolism contribute to the pathogenesis of the disease. We show here that transgenic expression in mice of GluR-B(N)-containing L-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptors with increased Ca(2+) permeability leads to late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progresses over the entire lifespan but manifests clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerates disease progression, aggravates the severity of motor decline, and decreases survival. These observations link persistently elevated Ca(2+) influx through AMPA channels with progressive motor decline and late-onset degeneration of spinal motoneurons, indicating that functionally altered AMPA channels may be causally related to pathogenesis of sporadic ALS in humans.
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PMID:Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit. 1582 16

Cu/Zn-superoxide dismutase 1 (SOD1), encoded on chromosome 21, is a key enzyme in metabolism of oxygen free radicals and oxidative stress. Transgenic mice overexpressing human SOD1 (Tg-hSOD1) are useful model for Down syndrome (trisomy 21) and familial amyotrophic lateral sclerosis (ALS). It was shown recently that Tg-hSOD1 mice develop a characteristic set of neurodegenerative changes in hippocampus and we therefore decided to study differential protein expression patterns, constructing a mouse hippocampal proteome map using two-dimensional electrophoresis (2-DE) with in-gel digestion of spots followed by matrix-assisted laser desorption/ionisation-time of flight (MALDI-TOF) identification and quantitatively compared protein profiles between non-transgenic mice, hemizygous and homozygous Tg-hSOD1 mice. In total 1056 spots were analysed, resulting in the identification of 445 polypeptides that were the products of 157 different genes. Among these a series of proteins involved in scaffolding, metabolism, signaling and other functions were deranged. Our findings suggest that overexpressed SOD1 directly or by generating reactive oxygen species may lead to aberrant protein expressional patterns that in turn may lead to or reflect neurodegeneration observed in this animal model.
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PMID:Proteome analysis in hippocampus of mice overexpressing human Cu/Zn-superoxide dismutase 1. 1586 42

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of spinal cord, brainstem, and cortical motor neurons. In a minority of patients, the disease is caused by mutations in the copper (2+)/zinc (2+) superoxide dismutase 1 (SOD1) gene. Recent evidence suggests that astrocytes are dysfunctional in ALS and may be a critical link in the support of motor neuron health. Furthermore, growth factors, such as glial cell line-derived neurotrophic factor (GDNF), have a high affinity for motor neurons and can prevent their death following various insults, but due to the protein's large size are difficult to directly administer to brain. In this study, human neural progenitor cells (hNPC) isolated from the cortex were expanded in culture and modified using lentivirus to secrete GDNF (hNPC(GDNF)). These cells survived up to 11 weeks following transplantation into the lumbar spinal cord of rats overexpressing the G93A SOD1 mutation (SOD1 (G93A)). Cellular integration into both gray and white matter was observed without adverse behavioral effects. All transplants secreted GDNF within the region of cell survival, but not outside this area. Fibers were seen to upregulate cholinergic markers in response to GDNF, indicating it was physiologically active. We conclude that genetically modified hNPC can survive, integrate, and release GDNF in the spinal cord of SOD1 (G93A) rats. As such, they provide an interesting source of cells for both glial replacement and trophic factor delivery in future human clinical studies.
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PMID:GDNF delivery using human neural progenitor cells in a rat model of ALS. 1587 82

Peroxiredoxin-ll (Prxll) and glutathione peroxidase-l (GPxl) are regulators of the redox system that is one of the most crucial supporting systems in neurons. This system is an antioxidant enzyme defense system and is synchronously linked to other important cell supporting systems. To clarify the common self-survival mechanism of the residual motor neurons affected by amyotrophic lateral sclerosis (ALS), we examined motor neurons from 40 patients with sporadic ALS (SALS) and 5 patients with superoxide dismutase 1 (SOD1)-mutated familial ALS (FALS) from two different families (frame-shift 126 mutation and A4 V) as well as four different strains of the SOD1-mutated ALS models (H46R/G93A rats and G1H/G1L-G93A mice). We investigated the immunohistochemical expression of Prxll/GPxl in motor neurons from the viewpoint of the redox system. In normal subjects, Prxll/GPxl immunoreactivity in the anterior horns of the normal spinal cords of humans, rats and mice was primarily identified in the neurons: cytoplasmic staining was observed in almost all of the motor neurons. Histologically, the number of spinal motor neurons in ALS decreased with disease progression. Immunohistochemically, the number of neurons negative for Prxll/GPxl increased with ALS disease progression. Some residual motor neurons coexpressing Prxll/GPxl were, however, observed throughout the clinical courses in some cases of SALS patients, SOD1-mutated FALS patients, and ALS animal models. In particular, motor neurons overexpressing Prxll/GPxl, i.e., neurons showing redox system up-regulation, were commonly evident during the clinical courses in ALS. For patients with SALS, motor neurons overexpressing Prxll/GPxl were present mainly within approximately 3 years after disease onset, and these overexpressing neurons thereafter decreased in number dramatically as the disease progressed. For SOD1-mutated FALS patients, like in SALS patients, certain residual motor neurons without inclusions also overexpressed Prxll/GPxl in the short-term-surviving FALS patients. In the ALS animal models, as in the human diseases, certain residual motor neurons showed overexpression of Prxll/GPxl during their clinical courses. At the terminal stage of ALS, however, a disruption of this common Prxll/GPxl-overexpression mechanism in neurons was observed. These findings lead us to the conclusion that the residual ALS neurons showing redox system up-regulation would be less susceptible to ALS stress and protect themselves from ALS neuronal death, whereas the breakdown of this redox system at the advanced disease stage accelerates neuronal degeneration and/or the process of neuronal death.
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PMID:Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models. 1598 30

Eliminating assembled neurofilaments (NFs) from axons or misaccumulating NFs in motor neuron cell bodies strongly slows disease in mouse models of mutant superoxide dismutase 1 (SOD1)-induced amyotrophic lateral sclerosis. One proposal for how reducing axonal NFs can increase survival is that the multiphosphorylated tail domains of the two larger NF subunits act in motor neuron cell bodies as phosphorylation sinks where they mitigate cyclin-dependent kinase 5 dysregulation induced by mutant SOD1. Elimination by gene targeting in mice of the NF medium and NF heavy tail domains and their 58 known phosphorylation sites accelerates aberrant phosphorylation of other neuronal substrates while leaving overall NF content unaltered. However, disease onset is significantly delayed and survival is extended, inconsistent with the ameliorative property of altered NF content protecting by serving as substrates for dysregulation of any NF kinase. Moreover, at comparable disease stages significantly more surviving motor neurons and axons were found in SOD1 mutant mice deleted in the NF tails than in similar mice with wild-type NFs. This finding supports noncell autonomous toxicity in SOD1 mutant-mediated amyotrophic lateral sclerosis: removal of the NF tails slows damage developed directly within motor neurons, but SOD1 mutant damage within nonneuronal supporting cells reduces motor neuron functionality.
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PMID:Altered axonal architecture by removal of the heavily phosphorylated neurofilament tail domains strongly slows superoxide dismutase 1 mutant-mediated ALS. 1600 69


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