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)

The immunohistochemical localization of glucose-regulated protein 78/BiP (GRP78), a chaperone protein that primarily resides within the lumen of the endoplasmic reticulum, was investigated in the lumbar spinal cord of mutant copper/zinc superoxide dismutase (SOD1) transgenic mice. Re-staining techniques were used to determine the immunoreactivity with anti-GRP78 antibody of abnormal structures observed by hematoxylin and eosin staining. Besides its physiological localization in the neuronal and glial cytoplasm, GRP78 was expressed in Lewy body-like hyaline inclusions, in irregularly-shaped eosinophilic structures without an apparent halo, and in cord-like swollen neurites. These different sites were invariably also immunopositive for ubiquitin, suggesting them to be pathological structures. The topographic distribution of GRP78 expression closely resembled that of SOD1. Moreover, our chronological quantitative analysis demonstrated that virtually all the Lewy body-like hyaline inclusions were immunolabeled by the anti-GRP78 antibody, irrespective to the age of mice examined, even at the presymptomatic stages. These findings imply that GRP78 may bind to, or at least be closely associated with, SOD1, and may participate in the pathological processes leading to inclusion formation. Thus, the results suggest that dysfunction of GRP78 and subsequent derangement of the system responding to unfolded proteins may be involved in the pathogenesis of familial amyotrophic lateral sclerosis caused by a mutation of the human SOD1 gene.
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PMID:Expression of an endoplasmic reticulum-resident chaperone, glucose-regulated stress protein 78, in the spinal cord of a mouse model of amyotrophic lateral sclerosis. 1623 Nov 59

To obtain insight into the morphological and molecular correlates of motoneuron degeneration in amyotrophic lateral sclerosis (ALS) mice that express G93A mutant superoxide dismutase (SOD)1 (G93A mice), we have mapped and characterized 'sick' motoneurons labelled by the 'stress transcription factors' ATF3 and phospho-c-Jun. Immunocytochemistry and in situ hybridization showed that a subset of motoneurons express ATF3 from a relatively early phase of disease before the onset of active caspase 3 expression and motoneuron loss. The highest number of ATF3-expressing motoneurons occurred at symptom onset. The onset of ATF3 expression correlated with the appearance of ubiquitinated neurites. Confocal double-labelling immunofluorescence showed that all ATF3-positive motoneurons were immunoreactive for phosphorylated c-Jun. Furthermore, the majority of ATF3 and phospho-c-Jun-positive motoneurons were also immunoreactive for CHOP (GADD153) and showed Golgi fragmentation. A subset of ATF3 and phosphorylated c-Jun-immunoreactive motoneurons showed an abnormal appearance characterized by a number of distinctive features, including an eccentric flattened nucleus, perikaryal accumulation of ubiquitin immunoreactivity, juxta-nuclear accumulation of the Golgi apparatus and the endoplasmic reticulum, and intense Hsp70 immunoreactivity. These abnormal cells were not immunoreactive for active caspase 3. We conclude that motoneurons in ALS-SOD1 mice prior to their death and disappearance experience a prolonged sick phase, characterized by the gradual accumulation of ubiquitinated material first in the neurites and subsequently the cell body.
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PMID:ATF3 expression precedes death of spinal motoneurons in amyotrophic lateral sclerosis-SOD1 transgenic mice and correlates with c-Jun phosphorylation, CHOP expression, somato-dendritic ubiquitination and Golgi fragmentation. 1626 28

The primary mechanism by which mutations in Cu, Zn-superoxide dismutase (SOD1) contribute to progressive motor neuron loss in familial amyotrophic lateral sclerosis (FALS) remains unknown. Misfolded protein aggregates, ubiquitin-proteasome system impairment and neuronal apoptosis mediated by death receptor or mitochondrial-dependent pathways are implicated in mutant SOD1-induced toxicity. Recent evidence from cellular and transgenic rodent models of FALS proposes activation of a third apoptotic pathway linked to sustained endoplasmic reticulum (ER) stress. Here, we review the emerging role of ER stress and the unfolded protein response (UPR) in the pathogenesis of mutant SOD1-linked FALS. The UPR observed in FALS rodents is described which encompasses induction of key ER-resident chaperones during presymptomatic disease, leading to activation of stress transducers and pro-apoptotic molecules by late stage disease. Importantly, mutant SOD1 co-aggregates with UPR components and recruits to the ER, suggesting a direct adverse effect on ER function. By contrast, the opposing neuroprotective effects of wild-type SOD1 overexpression on UPR signalling are also highlighted. In addition, the potential impact of neuronal Golgi apparatus (GA) fragmentation and subsequent disturbances in intracellular protein trafficking on motor neuron survival in FALS is also discussed. We propose that ER stress and UPR may be coupled to GA dysfunction in mutant SOD1-mediated toxicity, promoting ER-initiated cell death signalling in FALS.
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PMID:ER stress and UPR in familial amyotrophic lateral sclerosis. 1647 15

Accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) lumen induces ER stress. ER stress triggers the unfolded protein response (UPR), which includes the attenuation of general protein synthesis and the transcriptional activation of the genes encoding ER-resident chaperones and molecules involved in the ER-associated degradation (ERAD). The UPR coordinately reduces ER stress by restoration of the protein-folding capacity of the ER. However, severe and/or prolonged ER stress eventually leads cells to apoptosis. Several lines of evidence suggest that ER stress-induced apoptosis plays critical roles in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, polyglutamine (polyQ) diseases and amyotrophic lateral sclerosis (ALS). Apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPKKK family that constitutes the JNK and p38 MAP kinase (MAPK) cascades, is activated by physiological and cytotoxic stresses and induces various stress responses including apoptosis. Recent studies have shown that the ASK1-MAPK cascades are involved in ER stress-induced apoptosis and in the neuronal cell death in some model systems of neurodegenerative diseases. This review highlights the current understanding of regulatory mechanisms of ASK1 with a special focus on the ER stress-dependent and -independent neuronal cell death in the context of neurodegenerative diseases.
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PMID:The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. 1647 16

Fragmentation of the neuronal Golgi apparatus (GA) was reported in amyotrophic lateral sclerosis (ALS), corticobasal degeneration, Alzheimer's and Creutzfeldt-Jacob disease, and in spinocerebelar ataxia type 2 (SCA2). In transgenic mice expressing the G93A mutant of Cu/Zn superoxide dismutase (SOD1) of familial ALS (fALS), fragmentation of the GA of spinal cord motor neurons and aggregation of mutant protein were detected months before the onset of paralysis. Moreover, cells that expressed the G93A and G85R mutants of SOD1 showed fragmentation of the GA and decreased viability without apoptosis. We summarize here mechanisms involved in Golgi fragmentation implicating: (a) the dysregulation by mutant SOD1of the microtubule-destabilizing protein Stathmin, (b) the disruption by mutant SOD1of the neuronal cytoplasmic dynein, (c) the coprecipitation of mutant SOD1 with Hsp25 and Hsp27, (d) the reduction of detyrosinated microtubules by aggregated tau which resulted in non-apoptotic cell death and (e) the disruption by mutant growth hormone of the trafficking from the rough endoplasmic reticulum to the GA. The data indicate that neuronal Golgi fragmentation is an early and probably irreversible lesion in neurodegeneration, caused by a variety of mechanisms. Golgi fragmentation is not secondary to apoptosis but it may "trigger" apoptosis.
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PMID:Fragmentation of the Golgi apparatus in neurodegenerative diseases and cell death. 1654 97

Mutation in superoxide dismutase-1 (SOD1), which is a cause of ALS, alters the folding patterns of this protein. Accumulation of misfolded mutant SOD1 might activate endoplasmic reticulum (ER) stress pathways. Here we show that transgenic mice expressing ALS-linked SOD1 mutants exhibit molecular alterations indicative of a recruitment of ER's signaling machinery. We demonstrate by biochemical and morphological methods that mutant SOD1 accumulates inside the ER, where it forms insoluble high molecular weight species and interacts with the ER chaperone immunoglobulin-binding protein. These alterations are age- and region-specific, because they develop over the course of the disease and occur in the affected spinal cord but not in the nonaffected cerebellum in transgenic mutant SOD1 mice. Our results suggest a toxic mechanism for mutant SOD1 by which this ubiquitously expressed pathogenic protein could affect motor neuron survival and contribute to the selective motor neuronal degeneration in ALS.
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PMID:Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. 1659 34

Affinity purified IgG from sera of patients with amyotrophic lateral sclerosis (ALS) is claimed to enhance transmitter release, induce apoptotic death of cultured motoneurones, and elicit a distinctive cytopathology with raised Ca(2+) in mouse motoneurones. An alternative hypothesis attributes these events to serine proteases in ALS sera. To test this, motoneurones in BALB/c mice injected intraperitoneally with plasminogen affinity purified from sera of ALS patients and healthy controls were analysed using immunochemical and ultrastructural morphometric methods. The responses were validated in motoneurones of mice injected with commercially purified plasminogen, tissue plasminogen activator (tPA), or plasmin. Motoneurones in non-injected mice had normal morphology and ultrastructure without evidence of electron-dense degeneration. Purified plasminogen from both ALS patients and healthy controls, evoked electron-dense motoneurone degeneration, as did commercially purified plasminogen and tPA. The common cytopathology comprised disruption and distension of Nissl body rough endoplasmic reticulum, cytoplasmic polyribosomal proliferation, and significant Ca(2+) enhancement in mitochondria. By contrast, using affinity purified serum immunoglobulins, ALS-IgG but not IgG from healthy or disease controls, elicited necrosis, with 30% of ALS-IgGs tested evoking electron-dense degeneration in 40% of motoneurones. The primary cytopathology was extensive swelling of Golgi endoplasmic reticulum and mitochondria, with enhancement of Ca(2+) in Golgi endoplasmic reticulum and presynaptic boutons. We conclude that serine proteases purified from sera of ALS patients elicits a distinctive cytopathology and pattern of Ca(2+) enhancement in motoneurones different from that found on passive transfer of affinity purified ALS-IgG.
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PMID:Serine proteases purified from sera of patients with amyotrophic lateral sclerosis (ALS) induce contrasting cytopathology in murine motoneurones to IgG. 1659 43

Mutations in Cu/Zn superoxide dismutase (SOD1) are linked to motor neuron death in familial amyotrophic lateral sclerosis (ALS) by an unclear mechanism, although misfolded SOD1 aggregates are commonly associated with disease. Proteomic analysis of the transgenic SOD1(G93A) ALS rat model revealed significant up-regulation of endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI) family members in lumbar spinal cords. Expression of SOD1 mutants (mSOD1) led to an up-regulation of PDI in motor neuron-like NSC-34 cells but not other cell lines. Inhibition of PDI using bacitracin increased aggregate production, even in wild type SOD1 transfectants that do not readily form inclusions, suggesting PDI may protect SOD1 from aggregation. Moreover, PDI co-localized with intracellular aggregates of mSOD1 and bound to both wild type and mSOD1. SOD1 was also found in the microsomal fraction of cells despite being a predominantly cytosolic enzyme, confirming ER-Golgi-dependent secretion. In SOD1(G93A) mice, a significant up-regulation of unfolded protein response entities was also observed during disease, including caspase-12, -9, and -3 cleavage. Our findings therefore implicate unfolded protein response and ER stress-induced apoptosis in the patho-physiology of familial ALS. The possibility that PDI may be a therapeutic target to prevent SOD1 aggregation is also raised by this study.
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PMID:Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. 2871 Mar 40

Reticulons (RTNs) are a family of proteins that are primarily associated with the endoplasmic reticulum. In mammals, four genes have been identified and referred as to rtn1, 2, 3 and the neurite outgrowth inhibitor rtn4/nogo. These genes generate multiple isoforms that contain a common C-terminal reticulon homology domain of 150-200 amino-acid residues. The N-terminal regions of RTNs are highly variable, and result from alternative splicing or differential promoter usage. Although widely distributed, the functions of RTNs are still poorly understood. Much interest has been focused on rtn4/nogo because of its activity as a potent inhibitor of axonal growth and repair. In the present study, we update recent knowledge on mammalian RTNs paying special attention to the involvement of these proteins as markers of neurological diseases. We also present recent data concerning RTN expression in amyotrophic lateral sclerosis, a fatal degenerative disorder characterized by loss of upper and lower motor neurons, and muscle atrophy. The rearrangement of RTN expression is regulated not only in suffering skeletal muscle but also preceding the onset of symptoms, and may relate to the disease process.
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PMID:Reticulons as markers of neurological diseases: focus on amyotrophic lateral sclerosis. 1690 24

Riluzole is a drug used in the treatment of amyotrophic lateral sclerosis; however, its in vitro action is unclear. In this study, the effect of riluzole on intracellular Ca2+ concentration ([Ca2+]i) in Madin-Darby canine kidney (MDCK) cells was investigated using the Ca2+ -sensitive fluorescent dye, fura-2. Riluzole (100-500 microM) caused a rapid and sustained increase of [Ca2+]i in a concentration-dependent manner (EC50 = 150 microM). Some 40 and 50% of this [Ca2+]i increase was prevented by the removal of extracellular Ca2+ and the addition of La3+, respectively, but was unchanged by dihydropyridines, verapamil and diltiazem. In Ca2+ -free medium, thapsigargin - an inhibitor of the endoplasmic reticulum (ER) Caz+ -ATPase--caused a monophasic [Ca2+]i increase, after which the increasing effect of riluzole on [Ca2+]i was attenuated by 70%; in addition, pre-treatment with riluzole abolished thapsigargin-induced [Ca2+]i increases. U73122, an inhibitor of phospholipase C (PLC), abolished ATP (but not riluzole)-induced [Ca2+]i increases. At concentrations of 250 and 500 microM, riluzole killed 40 and 95% cells, respectively. The cytotoxic effect of riluzole (250 microM) was unaltered by pre-chelating cytosolic Ca2+ with BAPTA. Collectively, in MDCK cells, riluzole rapidly increased [Ca2+]i by stimulating extracellular Ca2+ influx via an La3+ -sensitive pathway and intracellular Ca2+ release from the ER via, as yet, unidentified mechanisms. Furthermore, riluzole caused Ca2+ -unrelated cytotoxicity in a concentration-dependent manner.
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PMID:Effect of riluzole on Ca2+ movement and cytotoxicity in Madin-Darby canine kidney cells. 1693 18


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