Methyl pyruvate rescues mitochondrial damage caused by SIGMAR1 mutation related to amyotrophic lateral sclerosis

Tagashira, Hideaki; Shinoda, Yasuharu; Shioda, Norifumi; Fukunaga, Kohji

doi:10.1016/j.bbagen.2014.08.012

Cited by 54 publications

(53 citation statements)

References 67 publications

(109 reference statements)

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“…One striking feature of the localization pattern of s-1R-E102Q was the presence of large, bright puncta, which colocalized poorly with the ER-resident protein BiP. Although little is known about the oligomerization dynamics of s-1R-E102Q, previous work has suggested that these puncta reflect cytosolic aggregates (Tagashira et al, 2014). Our data also suggest that these aggregates may reflect mutant s-1R clustering at ER subcompartments where BiP is excluded.…”

Section: Discussionsupporting

confidence: 56%

“…Moreover, subsequent work has demonstrated that the s-1R binds to binding immunoglobulin protein (BiP) when not activated by an agonist (Hayashi and Su, 2007a). However, the subcellular dynamics of the two s-1R mutants that underlie neuromuscular diseases, s-1R-E102Q (Tagashira et al, 2014) and s-1R-D31-50 (Li et al, 2015), are poorly characterized. We performed localization experiments using confocal imaging on primary MEF or CHO cells transiently transfected with the fluorescently tagged proteins s-1R-YFP and BiP-mCh to determine their intracellular localization.…”

Section: Resultsmentioning

confidence: 99%

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Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

et al. 2016

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The sigma-1 receptor (s-1R) is an endoplasmic reticulum resident chaperone protein involved in a plethora of cellular functions, and whose disruption has been implicated in a wide range of diseases. Genetic analysis has revealed two s-1R mutants involved in neuromuscular disorders. A point mutation (E102Q) in the ligand-binding domain results in the juvenile form of amyotrophic lateral sclerosis (ALS16), and a 20 amino-acid deletion (D31-50) in the putative cytosolic domain leads to a form of distal hereditary motor neuropathy. We investigated the localization and functional properties of these mutants in cell lines using confocal imaging and electrophysiology. The s-1R mutants exhibited a significant increase in mobility, aberrant localization, and enhanced block of the inwardly rectifying K 1 channel K ir 2.1, compared with the wild-type s-1R. Thus, these s-1R mutants have different functional properties that could contribute to their disease phenotypes.

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Section: Discussionsupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

et al. 2016

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“…Eventually, strategies to prevent ATP loss have been identified to exert an antioxidative stress effect [48]. Recently, MP accentuating ATP has also been regarded as a clinical approach to curing mitochondrial dysfunction due to mutated SIGMAR1, leading to amyotrophic lateral sclerosis [49].…”

Section: Discussionmentioning

confidence: 99%

Autophagy protein Ulk1 promotes mitochondrial apoptosis through reactive oxygen species

Mukhopadhyay

Das

Panda

et al. 2015

Free Radical Biology and Medicine

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“…For these genes, identified mutations comprised 20 % in SOD1 gene [6], 5 % in TARDBP and FUS genes [7], and more than 40 % in C9ORF72 [8]. In addition to these, mutations in alsin, senataxin (SETX), spatacsin, angiogenin (ANG), factor-induced gene 4 (FIG 4), optineurin (z), and sigma receptor 1 (SIGMAR1) have also been reported [9,10].…”

Section: Introductionmentioning

confidence: 91%

In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia

et al. 2015

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. It has been found to be associated with frontotemporal lobar degeneration (FTLD). In the present study, we have described homozygosity mapping and gene sequencing in a consanguineous autosomal recessive Pakistani family showing non-juvenile ALS without signs of FTLD. Gene mapping was carried out in all recruited family members using microsatellite markers, and linkage was established with sigma non-opioid intracellular receptor 1 (SIGMAR1) gene at chromosome 9p13.2. Gene sequencing of SIGMAR1 revealed a novel 3'-UTR nucleotide variation c.672*31A>G (rs4879809) segregating with disease in this family. The C9ORF72 repeat region in intron 1, previously implicated in a related phenotype, was excluded through linkage, and further confirmation of exclusion was obtained by amplifying intron 1 of C9ORF72 with multiple primers in affected individuals and controls. In silico analysis was carried out to explore the possible role of 3'-UTR variant of SIGMAR1 in ALS. The Regulatory RNA motif and Element Finder program revealed disturbance in miRNA (hsa-miR-1205) binding site due to this variation. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores due to this variation. Our results indicate that the 3'-UTR SIGMAR1 variant c.672*31A>G may have a role in the pathogenesis of ALS in this family.

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Methyl pyruvate rescues mitochondrial damage caused by SIGMAR1 mutation related to amyotrophic lateral sclerosis

Abstract: ATP supplementation by MP represents a potential therapeutic strategy to treat ALS caused by SIGMAR1 mutation.

Cited by 54 publications

References 67 publications

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

Autophagy protein Ulk1 promotes mitochondrial apoptosis through reactive oxygen species

In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia

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