Cited by 76Amyotrophic Lateral Sclerosis ResearchUbiquitin and proteasome pathwaysGenetic Neurodegenerative Diseases

Disturbance of proteasomal and autophagic protein degradation pathways by amyotrophic lateral sclerosis-linked mutations in ubiquilin 2

Osaka, Mayuko, Ito, Daisuke, Suzuki, Norihiro·2016·Biochemical and Biophysical Research Communications

Abstract

Ubiquilin (UBQLN), a member of the ubiquitin-like (UBL)-ubiquitin-associated (UBA) family, is a dual regulator of both the proteasomal and autophagic branches of the cellular protein degradation system. Mutations in the UBQLN2 gene encoding ubiquilin 2 cause X-linked amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), and UBQLN2-positive inclusions have been identified in ALS patients with UBQLN2 mutations as well as in cases of both familial and sporadic ALS without UBQLN2 mutations. Compelling evidence links UBQLN2 to disturbance of the protein quality control network in neurons, but the pathomechanisms remain obscure. This study aimed to clarify how ALS-linked mutations in UBQLN2 affect the protein degradation system. Overexpression of a UBQLN2 with ALS-associated mutations resulted in the accumulation of polyubiquitinated proteins in neuronal cells, including the ALS-associated protein TDP-43. This effect was dependent on the UBA domain but not on inclusion formation. Immunocytochemistry and protein fractionation analysis of IVm-UBQLN2 cellular distribution indicated that it sequesters ubiquitinated substrates from both the proteasomal and autophagic branches of the protein degradation system, resulting in accumulation of polyubiquitinated substrates. These findings provide a molecular basis for the development of ALS/FTD-associated proteinopathy and establish novel therapeutic targets for ALS.

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Crossref · 10.1016/j.bbrc.2016.02.107

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Authors
Osaka, M., Ito, D., & Suzuki, N.
Affiliations
Keio University (JP)
Corresponding author
Ito, Daisuke
Venue
Biochemical and Biophysical Research Communications
Publisher
Elsevier BV
Published
2016-04
Volume
472
Issue
2
Pages
324-331
ISSN
0006-291X (ISSN-L)
OpenAlex
W2289625033
Cited by
75
References
32
Citations by year
2026: 1 · 2025: 7 · 2024: 2 · 2023: 5 · 2022: 7 · 2021: 11 · 2020: 11 · 2019: 8 · 2018: 13 · 2017: 9 · 2016: 1
FWCI
7.77
Type
journal article
Language
en
Open access
closed
Locations
  • Biochemical and Biophysical Research Communications (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology of Japan (15J05597, 15579156)
  • life science foundation of Japan, Brain science foundation
  • Japan Amyotrophic Lateral Sclerosis Association
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
UBQLN2, amyotrophic lateral sclerosis, frontotemporal dementia, protein degradation, proteasome, autophagy, UBA domain, polyubiquitinated proteins, TDP-43, protein quality control, neuronal inclusions, therapeutic target
MeSH terms
Amyotrophic Lateral Sclerosis, Animals, Autophagy, Cell Line, Mutation, Neurons, Signal Transduction, Proteasome Endopeptidase Complex, Mice, Proteolysis

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