Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse model

Mitsui, Shun; Otomo, Asako; Nozaki, M; Ono, Suzuka; Sato, Kai; Shirakawa, Ryohei; Adachi, Hiroaki; Akiyama, Masashi; Sobue, Gen; Shang, Huifang; Hadano, Shinji

doi:10.1186/s13041-018-0373-8

Cited by 36 publications

(31 citation statements)

References 43 publications

(62 reference statements)

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“…However, many mouse models exist that demonstrate a relationship between p62 and other ALS genes. Mitsui et al (2018) previously reported that loss of SQSTM1 exacerbates disease phenotypes in SOD1H46R ALS mice. Following the initial report, the same authors demonstrated that SQSTM1 overexpression results in a significant increase in biochemically detectable insoluble SQSTM1 and poly-ubiquitinated proteins in the spinal cord of SQSTM1; SOD1H46R mice when compared to SOD1H46R mice.…”

Section: Sequestosome-1 (Sqstm1)mentioning

confidence: 93%

“…Following the initial report, the same authors demonstrated that SQSTM1 overexpression results in a significant increase in biochemically detectable insoluble SQSTM1 and poly-ubiquitinated proteins in the spinal cord of SQSTM1; SOD1H46R mice when compared to SOD1H46R mice. This observation suggests that overexpression of p62 in SOD1H46R mice accelerates disease onset by impairing the protein degradation pathways (Mitsui et al, 2018).…”

Section: Sequestosome-1 (Sqstm1)mentioning

confidence: 95%

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The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2020

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two diseases that form a broad neurodegenerative continuum. Considerable effort has been made to unravel the genetics of these disorders, and, based on this work, it is now clear that ALS and FTD have a significant genetic overlap. TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly C9orf72, are the critical genetic players in these neurological disorders. Discoveries of these genes have implicated autophagy, RNA regulation, and vesicle and inclusion formation as the central pathways involved in neurodegeneration. Here we provide a summary of the significant genes identified in these two intrinsically linked neurodegenerative diseases and highlight the genetic and pathological overlaps.

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Section: Sequestosome-1 (Sqstm1)mentioning

confidence: 93%

Section: Sequestosome-1 (Sqstm1)mentioning

confidence: 95%

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2020

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“…8,31 Owing to its role in protein degradation, overexpression of p62 has been shown to be protective in some neurodegenerative animal models, but overexpression in a SOD1 ALS model was found to accelerate disease onset. [32][33][34] Taken together, these studies suggest that a fine balance in p62 levels is required for optimal signaling and protein clearance. Consequently, small changes in Abbreviations: ALS = amyotrophic lateral sclerosis; fALS = familial ALS; I/D = insertion/deletion; sALS = sporadic ALS; SQSTM1 = sequestosome 1. a Each row compared using random effects to account for familial correlation.…”

Section: Discussionmentioning

confidence: 85%

Association of a structural variant within the SQSTM1 gene with amyotrophic lateral sclerosis

et al. 2020

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ObjectiveAs structural variations may underpin susceptibility to complex neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), the objective of this study was to investigate a structural variant (SV) within sequestosome 1 (SQSTM1). MethodsA candidate insertion/deletion variant within intron 5 of the SQSTM1 gene was identified using a previously established SV evaluation algorithm and chosen according to its subsequent theoretical effect on gene expression. The variant was systematically assessed through PCR, polyacrylamide gel fractionation, Sanger sequencing, and reverse transcriptase PCR. ResultsA reliable and robust assay confirmed the polymorphic nature of this variant and that the variant may influence SQSTM1 transcript levels. In a North American cohort of patients with familial ALS (fALS) and sporadic ALS (sALS) (n = 403) and age-matched healthy controls (n = 562), we subsequently showed that the SQSTM1 variant is associated with fALS (p = 0.0036), particularly in familial superoxide dismutase 1 mutation positive patients (p = 0.0005), but not with patients with sALS (p = 0.97). ConclusionsThis disease association highlights the importance and implications of further investigation into SVs that may provide new targets for cohort stratification and therapeutic development. sclerosis gene with amyotrophic lateral SQSTM1 Association of a structural variant within theThis information is current as of February 27, 2020 Services Updated Information & http://ng.neurology.org/content/6/2/e406.full.html including high resolution figures, can be found at: References http://ng.neurology.org/content/6/2/e406.full.html##ref-list-1 This article cites 38 articles, 4 of which you can access for free at: Subspecialty Collections http://ng.neurology.org//cgi/collection/association_studies_in_genetics Association studies in genetics http://ng.neurology.org//cgi/collection/amyotrophic_lateral_sclerosis_ Amyotrophic lateral sclerosis http://ng.neurology.org//cgi/collection/all_neuromuscular_disease All Neuromuscular Disease http://ng.neurology.org//cgi/collection/all_genetics All Genetics following collection(s): This article, along with others on similar topics, appears in the Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissions its entirety can be found online at: Information about reproducing this article in parts (figures,tables) or in Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsus Information about ordering reprints can be found online: reserved. Online

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“…E3 ubiquitin ligases, for example, have been linked to a wide range of neurodegenerative diseases; for a thorough review see George et al (2018). Alterations to protein degradation have been implicated in a broad spectrum of neurodegenerative conditions including PD, HD, Multiple Sclerosis and ALS (Mitra et al, 2009;Koch et al, 2015;Albert et al, 2017;Mitsui et al, 2018). UPS and autophagy have become increasingly pursued areas of study in conjunction with neurodegenerative and protein aggregation diseases (George et al, 2018;Kabir et al, 2020;Kumar et al, 2020;Lambert-Smith et al, 2020;Lim et al, 2020;Papanikolopoulou and Skoulakis, 2020;Tundo et al, 2020).…”

Section: Protein Degradation and Diseasementioning

confidence: 99%

Homeostatic Roles of the Proteostasis Network in Dendrites

Lottes

Cox

2020

Front. Cell. Neurosci.

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Cellular protein homeostasis, or proteostasis, is indispensable to the survival and function of all cells. Distinct from other cell types, neurons are long-lived, exhibiting architecturally complex and diverse multipolar projection morphologies that can span great distances. These properties present unique demands on proteostatic machinery to dynamically regulate the neuronal proteome in both space and time. Proteostasis is regulated by a distributed network of cellular processes, the proteostasis network (PN), which ensures precise control of protein synthesis, native conformational folding and maintenance, and protein turnover and degradation, collectively safeguarding proteome integrity both under homeostatic conditions and in the contexts of cellular stress, aging, and disease. Dendrites are equipped with distributed cellular machinery for protein synthesis and turnover, including dendritically trafficked ribosomes, chaperones, and autophagosomes. The PN can be subdivided into an adaptive network of three major functional pathways that synergistically govern protein quality control through the action of (1) protein synthesis machinery; (2) maintenance mechanisms including molecular chaperones involved in protein folding; and (3) degradative pathways (e.g., Ubiquitin-Proteasome System (UPS), endolysosomal pathway, and autophagy. Perturbations in any of the three arms of proteostasis can have dramatic effects on neurons, especially on their dendrites, which require tightly controlled homeostasis for proper development and maintenance. Moreover, the critical importance of the PN as a cell surveillance system against protein dyshomeostasis has been highlighted by extensive work demonstrating that the aggregation and/or failure to clear aggregated proteins figures centrally in many neurological disorders. While these studies demonstrate the relevance of derangements in proteostasis to human neurological disease, here we mainly review recent literature on homeostatic developmental roles the PN machinery plays in the establishment, maintenance, and plasticity of stable and dynamic dendritic arbors. Beyond basic housekeeping functions, we consider roles of PN machinery in protein quality control mechanisms linked to dendritic plasticity (e.g., dendritic spine remodeling during LTP); cell-type specificity; dendritic morphogenesis; and dendritic pruning.

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Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse model

Cited by 36 publications

References 43 publications

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Association of a structural variant within the SQSTM1 gene with amyotrophic lateral sclerosis

Homeostatic Roles of the Proteostasis Network in Dendrites

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