Mutations in the gene encoding p62 in Japanese patients with amyotrophic lateral sclerosis

Hirano, Minoru; Nakamura, Yusaku; Saigoh, Kazumasa; Sakamoto, Hikaru; Ueno, Shu‐ichi; Isono, Chiharu; Miyamoto, Katsuichi; Akamatsu, Maiko; Mitsui, Yosuke; Kusunoki, Susumu

doi:10.1212/wnl.0b013e31827f0fe5

Cited by 72 publications

(53 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analysis of all SQSTM1 variants that are predicted as being pathogenic in published cohorts, [3][4][5][6] and the current study demonstrated that pathogenic SQSTM1 variants are significantly associated with FALS with a combined odds ratio of 3.91 (P MH ¼ 0.0002, Supplementary Table 1). No significant association was found for SALS cases.…”

Section: Identification Of Sqstm1 Sequence Variants In a Uk-fals Cohortsupporting

confidence: 50%

“…[3][4][5][6] However, because of lack of DNA in multiple members of FALS kindred, to date it has not been proved that any of these mutations are transmitted with disease in ALS. Nevertheless, among the coding mutations is p.(Pro392Leu), which is common in Paget's disease of bone (PDB), 7,8 where there is evidence of transmission of the mutation with disease in multiple kindred.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB

2013

View full text Add to dashboard Cite

Mutations in the SQSTM1 gene have been reported to be associated with amyotrophic lateral sclerosis (ALS). We sought to determine the frequency of these mutations in a UK familial ALS ( Pro392Leu) carriers were heterozygous for a previously reported founder haplotype for PDB, where this mutation has an established causal effect. The frequency of the p.(Pro392Leu) mutation in this UK FALS cohort was 2.3% and 0.97% overall including three previously screened FALS cohorts. Our results confirm the presence of the p.(Pro392Leu) SQSTM1 mutation in FALS. This mutation is the most common SQSTM1 mutation found in ALS to date, and a likely pathogenicity is supported by having an established causal role in PDB. The occurrence of the same mutation in ALS and PDB is indicative of a common pathogenic pathway that converges on protein homeostasis.

show abstract

Section: Identification Of Sqstm1 Sequence Variants In a Uk-fals Cohortsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB

2013

View full text Add to dashboard Cite

show abstract

“…About 90 % of cases occur sporadically (sALS). The remainder are clearly familial (fALS; Valdmanis et al 2009); the genetic loci identified include genes encoding Cu/Zn-superoxide dismutase (SOD1; Rosen et al 1993), TAR DNA-binding protein 43 (Neumann et al 2006;Arai et al 2006), fused in sarcoma/ translated in liposarcoma (FUS; Kwiatkowski et al 2009;Vance et al 2009), vesicle-associated membrane protein B (Nishimura et al 2004), ubiquilin2 (Deng et al 2011), C9ORF72 (Renton et al 2011;Dejesus-Hernandez et al 2011), p62 (Hirano et al 2013), profilin 1 (Daoud et al 2013) , and RGNEF, a rhoGEF nucleotide exchange factor (Droppelmann et al 2013). Aside from sporadic ALS, this multiplicity of fALS-associated genes points to ALS being a syndrome with multiple initiating factors, yet there are commonalities in the manifestation of disease in patients with either familial or sporadic disease including formation of inclusions, unfolded protein responses, excitotoxicity, calcium dysregulation, mitochondrial dysfunction, oxidative stress, axonal transport defects, disruption of neuromuscular junctions, altered RNA metabolism, disruption of neuron-glia interactions, and inflammatory responses (Boillee et al 2006).…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo

Jieun

Louis

Tradewell

et al. 2014

Cell Stress and Chaperones

View full text Add to dashboard Cite

Heat shock proteins (HSPs) are attractive therapeutic targets for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), characterized by aberrant formation of protein aggregates. Although motor neurons have a high threshold for activation of HSP genes, HSP90 inhibitors are effective inducers. This study evaluated NXD30001, a novel, small molecule HSP90 inhibitor based on the radicicol backbone, for its ability to induce neuronal HSPs and for efficacy in an experimental model of ALS based on mutations in superoxide-dismutase 1 (SOD1). In motor neurons of dissociated murine spinal cord cultures, NXD30001-induced expression of HSP70/HSPA1 (iHSP70) and its co-chaperone HSP40/DNAJ through activation of HSF1 and exhibited a protective profile against SOD1 G93A similar to geldanamycin, but with less toxicity. Treatment prevented protein aggregation, mitochondrial fragmentation, and motor neuron death, important features of mutant SOD1 toxicity, but did not effectively prevent aberrant intracellular Ca 2+ accumulation. NXD30001 distributed to brain and spinal cord of wild-type and SOD1G93A transgenic mice following intraperitoneal injection; however, unlike in culture, in vivo levels of SOD1 were not reduced. NXD30001-induced expression of iHSP70 in skeletal and cardiac muscle and, to a lesser extent, in kidney, but not in liver, spinal cord, or brain, with either single or repeated administration. NXD30001 is a very useful experimental tool in culture, but these data point to the complex nature of HSP gene regulation in vivo and the necessity for early evaluation of the efficacy of novel HSP inducers in target tissues in vivo.

show abstract

“…Sequestosome 1 (SQSTM1) may represent another potential link between autophagy and ALS, as deletions and point mutations of this gene, encoding the ubiquitin-binding protein p62/SQSTM1, have been detected in ALS (Hirano et al, 2013;Teyssou et al, 2013). p62/SQSTM1 is a scaffold that acts as a mediator between ubiquitinated proteins and LC3-II in order to facilitate their removal via the autophagy (Matsumoto et al, 2011).…”

Section: Accumulation Of Als Pathogenetic Proteins and Autophagymentioning

confidence: 99%

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Mis

Brajkovic

Frattini

et al. 2016

Molecular and Cellular Neuroscience

View full text Add to dashboard Cite

a b s t r a c tAutophagy is a lysosome-dependant intracellular degradation process that eliminates long-lived proteins as well as damaged organelles from the cytoplasm. An increasing body of evidence suggests that dysregulation of this system plays a pivotal role in the etiology and/or progression of neurodegenerative diseases including motor neuron disorders. Herein, we review the latest findings that highlight the involvement of autophagy in the pathogenesis of amyotrophic lateral sclerosis (ALS) and the potential role of this pathway as a target of therapeutic purposes. Autophagy promotes the removal of toxic, cytoplasmic aggregate-prone pathogenetic proteins, enhances cell survival, and modulates inflammation. The existence of several drugs targeting this pathway can facilitate the translation of basic research to clinical trials for ALS and other motor neuron diseases..

show abstract

Mutations in the gene encoding p62 in Japanese patients with amyotrophic lateral sclerosis

Abstract: The presence of mutations in this racial population suggests worldwide, common involvement of the SQSTM1 gene in ALS.

Cited by 72 publications

References 31 publications

Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB

Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB

A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Contact Info

Product

Resources

About