Serine 403-phosphorylated p62/SQSTM1 immunoreactivity in inclusions of neurodegenerative diseases

Masaru Kurosawa; Gen Matsumoto; Hiroyuki Sumikura; Hiroyuki Hatsuta; Shigeo Murayama; Takashi Sakurai; Tomomi Shimogori; Nobutaka Hattori; Nobuyuki Nukina

doi:10.1016/j.neures.2015.08.002

Serine 403-phosphorylated p62/SQSTM1 immunoreactivity in inclusions of neurodegenerative diseases

Neurosci Res. 2016 Feb:103:64-70. doi: 10.1016/j.neures.2015.08.002. Epub 2015 Aug 21.

Authors

Masaru Kurosawa¹, Gen Matsumoto², Hiroyuki Sumikura³, Hiroyuki Hatsuta³, Shigeo Murayama³, Takashi Sakurai⁴, Tomomi Shimogori⁵, Nobutaka Hattori⁶, Nobuyuki Nukina⁷

Affiliations

¹ Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan; Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan; Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; CREST (Core Research for Evolutionary Science and Technology), JST, Tokyo 102-0076, Japan.
² Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan; Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan; CREST (Core Research for Evolutionary Science and Technology), JST, Tokyo 102-0076, Japan.
³ Department of Neurology & Neuropathology, Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology, Tokyo 173-0015, Japan.
⁴ Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
⁵ Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
⁶ Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
⁷ Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan; Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan; CREST (Core Research for Evolutionary Science and Technology), JST, Tokyo 102-0076, Japan; Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science, Kyoto 610-0394, Japan. Electronic address: nnukina@mail.doshisha.ac.jp.

PMID: 26302676
DOI: 10.1016/j.neures.2015.08.002

Abstract

Protein inclusions in neurodegenerative diseases are associated with p62, which has an important role in autophagic clearance of polyubiquitinated proteins. Selective autophagy is regulated by S403-phosphorylation of p62, and S403-phosphorylated p62 (S403-phos-p62) accumulates in Atg5 conditional knockout (Atg5CKO) mice in which autophagosome formation is impaired. We performed immunohistochemical tests for the presence of S403-phos-p62 in postmortem brain of neurodegenerative disease cases, and found accumulations in amyotrophic lateral sclerosis and Alzheimer's disease tissues. In Atg5CKO and HD190QG (Huntington's disease model) mice, however, we found a postmortem decrease in S403-phos-p62 immunoreactivity, suggesting that post-mortem changes should be considered when interpreting human data.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Dephosphorylation; Postmortem change; Protein degradation; Selective autophagy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Aged
Aged, 80 and over
Alzheimer Disease / metabolism*
Amyotrophic Lateral Sclerosis / metabolism*
Animals
Brain / metabolism
Heat-Shock Proteins / metabolism*
Humans
Huntingtin Protein
Huntington Disease / genetics
Huntington Disease / metabolism*
Intranuclear Inclusion Bodies / metabolism*
Mice, Mutant Strains
Middle Aged
Nerve Tissue Proteins / genetics
Nuclear Proteins / genetics
Phosphorylation
Postmortem Changes
Sequestosome-1 Protein

Substances

Adaptor Proteins, Signal Transducing
Heat-Shock Proteins
Htt protein, mouse
Huntingtin Protein
Nerve Tissue Proteins
Nuclear Proteins
Sequestosome-1 Protein
Sqstm1 protein, mouse
Sqstm1 protein, rat