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Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1^H46R-expressing ALS mouse model.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Recent studies have shown that mutations in SQSTM1 are linked to ALS. SQSTM1 encodes SQSTM1/p62 that regulates not only autophagy via the association with MAP1LC3/LC3 and ubiquitinated proteins but also the KEAP1-NFE2L2/Nrf2 anti-oxidative stress pathway by interacting with KEAP1. Previously, we have demonstrated that loss of SQSTM1 exacerbates disease phenotypes in a SOD1^H46R-expressing ALS mouse model. To clarify the effects of SQSTM1 overexpression in this model, we generated SQSTM1 and SOD1 ^H46R double-transgenic (SQSTM1;SOD1 ^H46R ) mice. SQSTM1;SOD1 ^H46R mice exhibited earlier disease onset and shorter lifespan than did SOD1 ^H46R mice. Conversely, disease progression after the onset rather slightly but significantly slowed in SQSTM1;SOD1 ^H46R mice. However, there were observable differences neither in the number of Nissl positive neurons nor in the distribution of ubiquitin-positive and/or SQSTM1-positive aggregates between SOD1 ^H46R and SQSTM1;SOD1 ^H46R mice. It was noted that these protein aggregates were mainly observed in neuropil, and partly localized to astrocytes and/or microglia, but not to MAP2-positive neuronal cell bodies and dendrites at the end-stage of disease. Nonetheless, the biochemically-detectable insoluble SQSTM1 and poly-ubiquitinated proteins were significantly and progressively increased in the spinal cord of SQSTM1;SOD1 ^H46R mice compared to SOD1 ^H46R mice. These results suggest that overexpression of SQSTM1 in SOD1 ^H46R mice accelerates disease onset by compromising the protein degradation pathways.

SUBMITTER: Mitsui S

PROVIDER: S-EPMC5975400 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1<sup>H46R</sup>-expressing ALS mouse model.

Mitsui Shun S Otomo Asako A Nozaki Masahisa M Ono Suzuka S Sato Kai K Shirakawa Ryohei R Adachi Hiroaki H Aoki Masashi M Sobue Gen G Shang Hui-Fang HF Hadano Shinji S

Molecular brain 20180529 1

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Recent studies have shown that mutations in SQSTM1 are linked to ALS. SQSTM1 encodes SQSTM1/p62 that regulates not only autophagy via the association with MAP1LC3/LC3 and ubiquitinated proteins but also the KEAP1-NFE2L2/Nrf2 anti-oxidative stress pathway by interacting with KEAP1. Previously, we have demonstrated that loss of SQSTM1 exacerbates diseas ...[more]

PMID: 29843805

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Project description:Macroautophagy (autophagy) is a key catabolic pathway for the maintenance of proteostasis through constant digestion of selective cargoes. The selectivity of autophagy is mediated by autophagy receptors that recognize and recruit cargoes to autophagosomes. SQSTM1/p62 is a prototype autophagy receptor, which is commonly found in protein aggregates associated with major neurodegenerative diseases. While accumulation of SQSTM1 implicates a disturbance of selective autophagy pathway, the pathogenic mechanism that contributes to impaired autophagy degradation remains poorly characterized. Herein we show that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)-linked mutations of TBK1 and SQSTM1 disrupt selective autophagy and cause neurotoxicity. Our data demonstrates that proteotoxic stress activates serine/threonine kinase TBK1, which coordinates with autophagy kinase ULK1 to promote concerted phosphorylation of autophagy receptor SQSTM1 at the UBA domain and activation of selective autophagy. In contrast, ALS-FTLD-linked mutations of TBK1 or SQSTM1 reduce SQSTM1 phosphorylation and compromise ubiquitinated cargo binding and clearance. Moreover, disease mutation SQSTM1G427R abolishes phosphorylation of Ser351 and impairs KEAP1-SQSTM1 interaction, thus diminishing NFE2L2/Nrf2-targeted gene expression and increasing TARDBP/TDP-43 associated stress granule formation under oxidative stress. Furthermore, expression of SQSTM1G427R in neurons impairs dendrite morphology and KEAP1-NFE2L2 signaling. Therefore, our results reveal a mechanism whereby pathogenic SQSTM1 mutants inhibit selective autophagy and disrupt NFE2L2 anti-oxidative stress response underlying the neurotoxicity in ALS-FTLD.Abbreviations: ALS: amyotrophic lateral sclerosis; FTLD: frontotemporal lobar degeneration; G3BP1: GTPase-activating protein (SH3 domain) binding protein 1; GSTM1: glutathione S-transferase, mu 1; HMOX/HO-1: Heme oxygenase 1; IP: immunoprecipitation; KEAP1: kelch-like ECH associated protein 1; KI: kinase inactive; KIR: KEAP1 interaction region; KO: knockout; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MBP: maltose binding protein; NBR1: NBR1, autophagy cargo receptor; NFE2L2/Nrf2: nuclear factor, erythroid derived 2, like 2; NQO1: NAD(P)H quinone dehydrogenase 1; SQSTM1/p62: sequestosome 1; SOD1: superoxide dismutase 1, soluble; S.S.: serum starvation; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK binding kinase 1; UBA: ubiquitin association; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type.

Dataset Information

Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1^H46R-expressing ALS mouse model.

Publications

Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1<sup>H46R</sup>-expressing ALS mouse model.

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Dataset Information

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

Publications

Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1<sup>H46R</sup>-expressing ALS mouse model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1^H46R-expressing ALS mouse model.