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)

A point mutation (P56S) in the vapb gene encoding an endoplasmic reticulum (ER)-integrated membrane protein [vesicle-associated membrane protein-associated protein B (VAPB)] causes autosomal-dominant amyotrophic lateral sclerosis. In our earlier study, we showed that VAPB may be involved in the IRE1/XBP1 signaling of the unfolded protein response, an ER reaction to inhibit accumulation of unfolded/ misfolded proteins, while P56S-VAPB formed insoluble aggregates and lost the ability to mediate the pathway (lossof- function), and suggested that P56S-VAPB promoted the aggregation of co-expressed wild-type (wt)-VAPB. In this study, a yeast inositol-auxotrophy assay has confirmed that P56S-VAPB is functionally a null mutant in vivo. The interaction between P56S-VAPB and wt-VAPB takes place with a high affinity through the major sperm protein domain in addition to the interaction through the C-terminal transmembrane domain. Consequently, wt-VAPB is speculated to preferentially interact with co-expressed P56S-VAPB, leading to the recruitment of wt-VAPB into cytosolic aggregates and the attenuation of its normal function. We have also found that expression of P56S-VAPB increases the vulnerability of NSC34 motoneuronal cells to ER stress-induced death. These results lead us to hypothesize that the total loss of VAPB function in unfolded protein response, induced by one P56S mutant allele, may contribute to the development of P56SVAPB- induced amyotrophic lateral sclerosis.
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PMID:ALS-linked P56S-VAPB, an aggregated loss-of-function mutant of VAPB, predisposes motor neurons to ER stress-related death by inducing aggregation of co-expressed wild-type VAPB. 1918 64

Mutations in the gene encoding vesicle-associated membrane protein (VAPB) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. The VAPB gene is mapped to chromosome number 20 and can be found at cytogenetic location 20q13.33 of the chromosome. VAPB is seen to play a significant role in the unfolded protein response (UPR), which is a process that suppresses the accumulation of unfolded proteins in the endoplasmic reticulum. Earlier studies have reported two points; which we have analyzed in our study. Firstly, the mutation P56S in the VAPB is seen to increase the stability of the protein and secondly, the mutation P56S in VAPB is seen to interrupt the functioning of the gene and loses its ability to be involved in the activation of the IRE1/XBP1 pathway which leads to ALS. With correlation on the previous research studies on the stability of this protein, we carried out Molecular dynamics (MD) simulation. We analyzed the SNP results of 17 nsSNPs obtained from dbSNP using SIFT, polyphen, I-Mutant, SNP&GO, PhDSNP and Mutpred to predict the role of nsSNPs in VAPB. MD simulation is carried out and plots for RMSD, RMSF, Rg, SASA, H-bond and PCA are obtained to check and prove the stability of the wild type and the mutant protein structure. The protein is checked for its aggregation and the results obtained show changes in the protein structure that might result in the loss of function.
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PMID:Protein aggregation due to nsSNP resulting in P56S VABP protein is associated with amyotrophic lateral sclerosis. 2468 3

The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER) to a disturbance in protein folding. The so-called ER stress sensors PERK, IRE1 and ATF6 play a central role in the initiation and regulation of the UPR. The accumulation of misfolded and aggregated proteins is a common characteristic of neurodegenerative diseases. With the discovery of the basic machinery of the UPR, the idea was born that the UPR or part of its machinery could be involved in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prion disease. Over the last decade, the UPR has been addressed in an increasing number of studies on neurodegeneration. The involvement of the UPR has been investigated in human neuropathology across different neurological diseases, as well as in cell and mouse models for neurodegeneration. Studies using different disease models display discrepancies on the role and function of the UPR during neurodegeneration, which can often be attributed to differences in methodology. In this review, we will address the importance of investigation of human brain material for the interpretation of the role of the UPR in neurological diseases. We will discuss evidence for UPR activation in neurodegenerative diseases, and the methodology to study UPR activation and its connection to brain pathology will be addressed. More recently, the UPR is recognized as a target for drug therapy for treatment and prevention of neurodegeneration, by inhibiting the function of specific mediators of the UPR. Several preclinical studies have shown a proof-of-concept for this approach targeting the machinery of UPR, in particular the PERK pathway, in different models for neurodegeneration and have yielded paradoxical results. The promises held by these observations will need further support by clarification of the observed differences between disease models, as well as increased insight obtained from human neuropathology.
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PMID:The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. 2621 Sep 90

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that affects upper and lower motor neurons. Since motor neurons target skeletal muscles, the maintenance system of muscles is disturbed in ALS; however, the mechanism by which this occurs is unknown. In the present study, we investigated the effects of ALS-associated P56S-vesicle-associated membrane protein-associated protein B (VAPB) (P56S-VAPB) on the IRE1-XBP1 pathway, which is involved in the unfolded protein response (UPR) of the mouse myoblast cell line (C2C12 cells). Experiments with C2C12 cells transfected with wild-type wt-VAPB and P56S-VAPB expression vectors showed reduced myotube formation and aberrant myonuclear position in cells expressing P56S-VAPB. Activity of the IRE1-XBP1 pathway in the cells visualized with the ERAI system revealed that the pathway was disrupted in cells expressing P56S-VAPB, whereas the IRE1-XBP1 pathway activity was enhanced in the differentiation process of normal C2C12 cells. These results suggest that disruption of the IRE1-XBP1 pathway is a cause for the reduced myotube formation in P56S-VAPB-expressing cells. The expression level of the VAPB protein has been reported to be reduced in the neurons of patients with ALS. Therefore, it is expected that the IRE1-XBP1 pathway is also impaired in muscle tissues of patients with ALS, which causes a disturbance in the muscle maintenance system.
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PMID:ALS-Linked P56S-VAPB Mutation Impairs the Formation of Multinuclear Myotube in C2C12 Cells. 2626 7

The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X-ALD), a neurometabolic disorder that is caused by ABCD1 malfunction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein aggregates. Using X-ALD mouse model (Abcd1 - and Abcd1 - /Abcd2 -/- mice) and X-ALD patient's fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis during ER stress induced in X-ALD fibroblasts. Redox imbalance appears to be the mechanism that initiates ER stress in X-ALD. Most importantly, we demonstrated that the bile acid tauroursodeoxycholate (TUDCA) abolishes UPR activation, which results in improvement of axonal degeneration and its associated locomotor impairment in Abcd1 - /Abcd2 -/- mice. Altogether, our preclinical data provide evidence for establishing the UPR as a key drug target in the pathogenesis cascade. Our study also highlights the potential role of TUDCA as a treatment for X-ALD and other axonopathies in which similar molecular mediators are implicated.
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PMID:Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy. 2800 77

Loss of protein folding homeostasis features many of the most prevalent neurodegenerative disorders. As coping mechanism to folding stress within the endoplasmic reticulum (ER), the unfolded protein response (UPR) comprises a set of signaling mechanisms that initiate a gene expression program to restore proteostasis, or when stress is chronic or overwhelming promote neuronal death. This fate-defining capacity of the UPR has been proposed to play a key role in amyotrophic lateral sclerosis (ALS). However, the several genetic or pharmacological attempts to explore the therapeutic potential of UPR modulation have produced conflicting observations. In order to establish the precise relationship between UPR signaling and neuronal death in ALS, we have developed a neuronal model where the toxicity of a familial ALS-causing allele (mutant G93A SOD1) and UPR activation can be longitudinally monitored in single neurons over the process of neurodegeneration by automated microscopy. Using fluorescent UPR reporters we established the temporal and causal relationship between UPR and neuronal death by Cox regression models. Pharmacological inhibition of discrete UPR processes allowed us to establish the contribution of PERK (PKR-like ER kinase) and IRE1 (inositol-requiring enzyme-1) mechanisms to neuronal fate. Importantly, inhibition of PERK signaling with its downstream inhibitor ISRIB, but not with the direct PERK kinase inhibitor GSK2606414, significantly enhanced the survival of G93A SOD1-expressing neurons. Characterization of the inhibitory properties of both drugs under ER stress revealed that in neurons (but not in glial cells) ISRIB overruled only part of the translational program imposed by PERK, relieving the general inhibition of translation, but maintaining the privileged translation of ATF4 (activating transcription factor 4) messenger RNA. Surprisingly, the fine-tuning of the PERK output in G93A SOD1-expressing neurons led to a reduction of IRE1-dependent signaling. Together, our findings identify ISRIB-mediated translational reprogramming as a new potential ALS therapy.
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PMID:Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis. 3245 86