ArticleMolecular and cellular biology2013
Regulation of feedback between protein kinase A and the proteasome system worsens Huntington's disease.
Article in Molecular and cellular biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 2 of them syntheses that pooled it.
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Who cites it
43 citing papers in PubMed, 2 syntheses or guidelines pooled it, 70 citations in OpenAlex.
- The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.Pharmacology & therapeutics · 2020Pooled it
- The Heart of the Alzheimer's: A Mindful View of Heart Disease.Frontiers in physiology · 2020Pooled it
- Allosteric modulation of protein kinase A in individuals affected by NLPD-PKA, a neurodegenerative disease in which the PRKAR1B L50R variant is expressed.The FEBS journal · 2025Article
- Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics.Neuron · 2025Article
- Aberrant phase separation of two PKA RIβ neurological disorder mutants leads to mechanistically distinct signaling deficits.Cell reports · 2025Article
- Mechanistic insights on the role of Nrf-2 signalling in Huntington's disease.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Review
- Early disruption of the CREB pathway drives dendritic morphological alterations in FTD/ALS cortical neurons.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Neuropathogenesis-on-chips for neurodegenerative diseases.Nature communications · 2024Review
- Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases.Archives of toxicology · 2024Review
- Dysfunction of cAMP-Protein Kinase A-Calcium Signaling Axis in Striatal Medium Spiny Neurons: A Role in Schizophrenia and Huntington's Disease Neuropathology.Biological psychiatry global open science · 2023Article
- Cell Rearrangement and Oxidant/Antioxidant Imbalance in Huntington's Disease.Antioxidants (Basel, Switzerland) · 2023Review
- Nrf2 Pathway in Huntington's Disease (HD): What Is Its Role?International journal of molecular sciences · 2022Review
- PKR Protects the Major Catalytic Subunit of PKA Cpk1 from FgBlm10-Mediated Proteasome Degradation inInternational journal of molecular sciences · 2022Article
- Mechanisms That Activate 26S Proteasomes and Enhance Protein Degradation.Biomolecules · 2021Review
- A Putative Role for Ubiquitin-Proteasome Signaling in Estrogenic Memory Regulation.Frontiers in behavioral neuroscience · 2021Article
- Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities.Nature reviews. Neurology · 2020Review
- Oxyphylla A Promotes Degradation of α-Synuclein for NeuroprotectionAging and disease · 2020Article
- Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- CTIP2-Regulated Reduction in PKA-Dependent DARPP32 Phosphorylation in Human Medium Spiny Neurons: Implications for Huntington Disease.Stem cell reports · 2019Article
- Proteasome-Dependent Regulation of Distinct Metabolic States During Long-Term Culture of Human iPSC-Derived Cardiomyocytes.Circulation research · 2019Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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