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

Molecular Brain
Shun MitsuiShinji Hadano

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 SOD1H46R-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 m...Continue Reading

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Citations

Feb 13, 2020·Cells·Emiliano VicencioUte Woehlbier
Mar 3, 2020·Frontiers in Neuroscience·Yevgeniya A AbramzonRuth Chia
Jul 1, 2020·Neural Regeneration Research·Adriana Delice Foster, Sarah Lyn Rea
Oct 6, 2020·Frontiers in Cellular Neuroscience·Erin N Lottes, Daniel N Cox
Jan 28, 2021·International Journal of Molecular Sciences·Hilal CihankayaVeronika Matschke
Dec 2, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Jun-Ling Wang, Chao-Jin Xu

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Methods Mentioned

BETA
transgenic
PCR
Protein Assay
electrophoresis

Software Mentioned

Prism
Dynamic
CS Analyzer
Lifespan

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