Rho Kinase Pathway Alterations in the Brain and Leukocytes in Huntington's Disease.
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.
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School, Massachusetts General Hospital, East, Bldg 114, Room 2005, Charlestown, MA, 02129-4404, USA.
K Lakshmi
KL
Narayanan
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School, Massachusetts General Hospital, East, Bldg 114, Room 2005, Charlestown, MA, 02129-4404, USA.
Vanita
V
Chopra
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School, Massachusetts General Hospital, East, Bldg 114, Room 2005, Charlestown, MA, 02129-4404, USA.|Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, 02129, USA.|Center for Neuroimaging of Aging and Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
H Diana
HD
Rosas
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School, Massachusetts General Hospital, East, Bldg 114, Room 2005, Charlestown, MA, 02129-4404, USA.|Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, 02129, USA.|Center for Neuroimaging of Aging and Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
Keith
K
Malarick
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School, Massachusetts General Hospital, East, Bldg 114, Room 2005, Charlestown, MA, 02129-4404, USA. hersch@helix.mgh.harvard.edu.
Steven
S
Hersch
D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D006816:Huntington Disease / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D007962:Leukocytes / Q000201:enzymology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D011180:Postmortem Changes; D051304:Profilins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
D051339:Actin Depolymerizing Factors; D051304:Profilins; D054460:rho-Associated Kinases
Biomarker; Huntington’s disease; Rho kinase pathway; mRNA expression