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Cited by 70Genetic Neurodegenerative DiseasesLysosomal Storage Disorders ResearchHeat shock proteins research

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

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Lin, Jiun-Tsai, Chang, Wei-Cheng, Chen, Hui-Mei, Lai, Hsing-Lin, Chen, Chih-Yeh, Tao, Mi-Hua, Chern, Yijuang·2013·Molecular and Cellular Biology
DOI 10.1128/mcb.01434-12PMC PMC3623082
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Abstract

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG repeat in the Huntingtin (HTT) gene. Abnormal regulation of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway occurs during HD progression. Here we found that lower PKA activity was associated with proteasome impairment in the striatum for two HD mouse models (R6/2 and N171-82Q) and in mutant HTT (mHTT)-expressing striatal cells. Because PKA regulatory subunits (PKA-Rs) are proteasome substrates, the mHTT-evoked proteasome impairment caused accumulation of PKA-Rs and subsequently inhibited PKA activity. Conversely, activation of PKA enhanced the phosphorylation of Rpt6 (a component of the proteasome), rescued the impaired proteasome activity, and reduced mHTT aggregates. The dominant-negative Rpt6 mutant (Rpt6(S120A)) blocked the ability of a cAMP-elevating reagent to enhance proteasome activity, whereas the phosphomimetic Rpt6 mutant (Rpt6(S120D)) increased proteasome activity, reduced HTT aggregates, and ameliorated motor impairment. Collectively, our data demonstrated that positive feedback regulation between PKA and the proteasome is critical for HD pathogenesis.

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  • Blocking phosphorylation of Rpt6 at S120 sensitizes yeast and mice to pathogenic effects of Huntington protein aggregation.

    “Furthermore, blocking phosphorylation of Rpt6 at S120 appears to sensitize both yeast and mice to pathogenic effects of Huntington protein aggregation”

    From Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning (2021) · cites this paper as Lin et al., 2013

    The Results (page unavailable) show that nonphosphorylatable Rpt6S120A blocked a treatment’s reduction of mutant huntingtin aggregates in striatal cells. In mice, the paper tested the opposite manipulation: phosphomimetic Rpt6S120D reduced aggregates and motor impairment. The cited passages do not establish that blocking S120 phosphorylation sensitized yeast or mice. (LLM, conf=0.88)

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Sorted by citations

Authors
Lin, J.-T., Chang, W.-C., Chen, H.-M., Lai, H.-L., Chen, C.-Y., Tao, M.-H., & Chern, Y.
Affiliations
  • Institute of Biomedical Sciences, Academia Sinica (TW)
  • Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2013-03-01
Volume
33
Issue
5
Pages
1073-1084
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.01434-12
PMC
PMC3623082
OpenAlex
W2096597463
Cited by
70
References
4
Citations by year
2025: 5 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 10 · 2016: 1 · 2015: 8 · 2014: 7 · 2013: 3
FWCI
2.37
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Council
  • National Institutes of Health
  • National Institute of Mental Health
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
Huntington's disease, protein kinase A, proteasome, Rpt6, positive feedback regulation, mutant huntingtin, huntingtin aggregation, striatum, cAMP signaling, PKA regulatory subunit, motor impairment, R6/2 mice
MeSH terms
Huntingtin Protein, Animals, Cell Line, Corpus Striatum, Enzyme Activation, Female, Huntington Disease, Male, Motor Activity, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Cyclic AMP-Dependent Protein Kinases, Proteasome Endopeptidase Complex, Mice, Rats

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