Depletion of p62 reduces nuclear inclusions and paradoxically ameliorates disease phenotypes in Huntington's model mice
Abstract
Huntington's disease (HD) is a dominantly inherited genetic disease caused by mutant huntingtin (htt) protein with expanded polyglutamine (polyQ) tracts. A neuropathological hallmark of HD is the presence of neuronal inclusions of mutant htt. p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. Here, we investigated the effect of p62 depletion in three HD model mice: R6/2, HD190QG and HD120QG mice. We found that loss of p62 in these models led to longer life spans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyQ length. In mouse embryonic fibroblasts (MEFs) with or without p62, mutant htt with a nuclear localization signal (NLS) showed no difference in nuclear inclusion between the two MEF types. In the case of mutant htt without NLS, however, p62 depletion increased cytoplasmic inclusions. Furthermore, to examine the effect of impaired autophagy in HD model mice, we crossed R6/2 mice with Atg5 conditional knockout mice. These mice also showed decreased nuclear inclusions and increased cytoplasmic inclusions, similar to HD mice lacking p62. These data suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions.
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p62 inclusion bodies are an important phenotypic HD marker of disease progression.
“Analysis of brain tissues revealed almost 40% silencing of the Htt gene in mouse brain cortex and a highly significant decrease of p62 inclusion bodies in the cortical neurons of the treated animals, an important phenotypic HD marker of disease progression (Fig. 4e, f).”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [56]
The Abstract calls neuronal inclusions of mutant huntingtin a neuropathological hallmark of HD. The section on nuclear inclusion formation reports changes in inclusions with age in HD model mice, but it does not establish that p62 inclusion bodies specifically are a marker of disease progression. Page numbers were not supplied for these passages. (LLM, conf=0.83)
Experimental — accuracy not yet measuredA reduction in p62 aggregates in HD mouse models has previously been shown to restore HD-associated phenotypes.
“p62 is an important regulatory protein of selective autophagy, and a reduction in p62 aggregates in HD mouse models has previously been shown to restore HD-associated phenotypes56.”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [56]
The Discussion reports that genetic ablation of p62 ameliorated disease phenotypes in three HD mouse models and reduced nuclear inclusions. It does not report that reducing p62 aggregates restored the phenotypes: the reduced nuclear inclusions were of mutant huntingtin, and the reported phenotypes improved rather than fully recovered. (LLM, conf=0.87)
Experimental — accuracy not yet measuredp62 is an important regulatory protein of selective autophagy.
“p62 is an important regulatory protein of selective autophagy, and a reduction in p62 aggregates in HD mouse models has previously been shown to restore HD-associated phenotypes56.”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [56]
Mutant huntingtin accumulates in many cell types and in multiple forms, due at least in part to failure of protein quality control networks, as reflected by accumulation of ubiquitin and other post-translationally-modified proteins and disruptions in autophagy.
“Pathologically, mHTT accumulates in many cells types, and in multiple forms, due at least in part to the failure of protein quality control networks, as reflected by an accumulation of ubiquitin and other post-translationally-modified proteins (Ochaba et al. , 2016) and disruptions in autophagy (Kurosawa et al. , 2015).”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Kurosawa et al., 2015
In R6/2 mice, the autophagic protein p62 co-localized with EM48+ inclusion bodies.
“co-localization of the autophagic protein p62 with EM48 + inclusion bodies in R6/2 mice”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Kurosawa et al., 2015
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- Authors
- Kurosawa, M., Matsumoto, G., Kino, Y., Okuno, M., Kurosawa-Yamada, M., Washizu, C., Taniguchi, H., Nakaso, K., Yanagawa, T., Warabi, E., Shimogori, T., Sakurai, T., Hattori, N., & Nukina, N.
- Affiliations
- RIKEN Center for Brain Science (JP)
- Tottori University (JP)
- University of Tsukuba (JP)
- Juntendo University (JP)
- Corresponding author
- Nukina, Nobuyuki
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-10-09
- Volume
- 24
- Issue
- 4
- Pages
- 1092-1105
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2115926962
- Cited by
- 63
- References
- 34
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 13 · 2020: 7 · 2019: 6 · 2018: 4 · 2017: 4 · 2016: 5 · 2015: 6
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (25253066, 22110004, CREST, 22240037)
- Japan Society for the Promotion of Science (24659436, 23300128, 23500434)
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Huntington's disease, p62, selective autophagy, mutant huntingtin, polyglutamine, intranuclear inclusions, cytoplasmic inclusions, R6/2 mice, nuclear localization signal, lifespan, neurodegeneration
- MeSH terms
- Animals, Autophagy, Corpus Striatum, Disease Models, Animal, Female, Hippocampus, Huntington Disease, Longevity, Peptides, Phenotype, Mice, Knockout, Intracellular Space, Intranuclear Inclusion Bodies, Adaptor Proteins, Signal Transducing, Mice, Proteolysis
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