Rho Kinase Pathway Alterations in the Brain and Leukocytes in Huntington’s Disease
Open accessAbstract
Huntington's disease (HD) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the huntingtin gene. Therapeutic approaches targeting mutant huntingtin (mtHtt) or its downstream toxic consequences are under development, including Rho kinase pathway inhibition. We investigated the messenger RNA (mRNA) expression of Rho kinase pathway genes, including RhoA (Ras homolog family member A), ROCK1 (Rho-associated kinase1), PRK2 (protein kinase C-related protein kinase 2), Profilin1, cofilin1, MYPT1 (myosin phosphatase target subunit 1), and LIMK1 (LIM domain kinase 1) in HD human blood leukocytes, postmortem brain, and in R6/2 HD mouse brain tissue using qPCR. RhoA, ROCK1, PRK2, Profilin1, cofilin1, and MYPT1 were significantly increased in HD blood compared to controls. In frontal cortex of HD postmortem brain tissue, the expression of RhoA, ROCK1, PRK2, Profilin1, and MYPT1 were also significantly increased. In the brain from 4-week-old R6/2 mice, the expression of Rock1, Prk2, Cofilin1, and MYPT1 was significantly increased while RhoA, Rock1, Profilin1, Cofilin1, and Mypt1 were increased and Limk1 mRNA decreased in 13-week-old R6/2 mice. Western blot analysis using human postmortem tissues for ROCK1 and Profilin1 demonstrated significantly increased protein levels, which correlated with the mRNA increases. Collectively, we have shown the panel of Rho kinase pathway genes to be highly altered in human HD blood, postmortem brain tissue, and in R6/2 mice. These studies confirm that HD upregulates the Rho kinase pathway and identifies mRNAs that could serve as peripheral markers in HD patients and translational markers in HD mouse models.
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In blood samples and frontal cortex of postmortem brain tissue from HD patients as well as in the striatum of the R6/2 HD mouse model, mRNA expression levels of RhoA, ROCK, and a number of downstream cytoskeletal-related effector proteins are upregulated.
“In blood samples and frontal cortex of postmortem brain tissue from HD patients as well as in the striatum of the R6/2 HD mouse model, mRNA expression levels of RhoA, ROCK, and a number of downstream cytoskeletal-related effector proteins were upregulated [207].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [207]
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Research works printed but not linked: 20
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Denis, H. L., Lamontagne-Proulx, J., St-Amour, I., Mason, S. L., Weiss, A., Chouinard, S., Barker, R. A., Boilard, E., & Cicchetti, F. (2018) · Journal of Neurology · doi:10.1007/s00415-018-9022-5 · Cited by 32 · see citing works
- Authors
- Narayanan, K. L., Chopra, V., Rosas, H. D., Malarick, K., & Hersch, S.
- Affiliations
- Harvard University (US)
- Corresponding author
- Hersch, Steven
- Venue
- Molecular Neurobiology
- Published
- 2015-05-05
- Volume
- 53
- Issue
- 4
- Pages
- 2132-2140
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- PMC
- PMC4823347
- OpenAlex
- W2016318920
- Cited by
- 37
- References
- 0
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 3 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 1
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Neurobiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Massachusetts General Hospital
- Neurological Foundation of New Zealand
- National Institute of Neurological Disorders and Stroke (P01NS058793, R56NS042861)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Huntington's disease, RhoA, ROCK1, PRK2, profilin-1, cofilin-1, MYPT1, LIMK1, mutant huntingtin, blood leukocytes, postmortem brain, R6/2 mice, mRNA expression, peripheral biomarkers, neurodegeneration
- MeSH terms
- Adult, Aged, Animals, Brain, Disease Models, Animal, Female, Frontal Lobe, Gene Expression Regulation, Humans, Huntington Disease, Leukocytes, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Postmortem Changes, Blotting, Western, Signal Transduction, Profilins, Actin Depolymerizing Factors, rho-Associated Kinases
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