TY - JOUR
T1 - Quantitative Proteomic Analysis Reveals Similarities between Huntington's Disease (HD) and Huntington's Disease-Like 2 (HDL2) Human Brains
AU - Ratovitski, Tamara
AU - Chaerkady, Raghothama
AU - Kammers, Kai
AU - Stewart, Jacqueline C.
AU - Zavala, Anialak
AU - Pletnikova, Olga
AU - Troncoso, Juan C.
AU - Rudnicki, Dobrila D.
AU - Margolis, Russell L.
AU - Cole, Robert N.
AU - Ross, Christopher A.
N1 - Funding Information:
T.R. and C.R. also received support from NINDS (5R01 NS076631). The human tissue brain bank is supported in part by Johns Hopkins Alzheimers Disease Research Center (P50AG05146). O.P. and J.C.T. received support from BrightFocus Foundation (grant no. A2015332S).
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/9/2
Y1 - 2016/9/2
N2 - The pathogenesis of HD and HDL2, similar progressive neurodegenerative disorders caused by expansion mutations, remains incompletely understood. No systematic quantitative proteomics studies, assessing global changes in HD or HDL2 human brain, were reported. To address this deficit, we used a stable isotope labeling-based approach to quantify the changes in protein abundances in the cortex of 12 HD and 12 control cases and, separately, of 6 HDL2 and 6 control cases. The quality of the tissues was assessed to minimize variability due to post mortem autolysis. We applied a robust median sweep algorithm to quantify protein abundance and performed statistical inference using moderated test statistics. 1211 proteins showed statistically significant fold changes between HD and control tissues; the differences in selected proteins were verified by Western blotting. Differentially abundant proteins were enriched in cellular pathways previously implicated in HD, including Rho-mediated, actin cytoskeleton and integrin signaling, mitochondrial dysfunction, endocytosis, axonal guidance, DNA/RNA processing, and protein transport. The abundance of 717 proteins significantly differed between control and HDL2 brain. Comparative analysis of the disease-associated changes in the HD and HDL2 proteomes revealed that similar pathways were altered, suggesting the commonality of pathogenesis between the two disorders.
AB - The pathogenesis of HD and HDL2, similar progressive neurodegenerative disorders caused by expansion mutations, remains incompletely understood. No systematic quantitative proteomics studies, assessing global changes in HD or HDL2 human brain, were reported. To address this deficit, we used a stable isotope labeling-based approach to quantify the changes in protein abundances in the cortex of 12 HD and 12 control cases and, separately, of 6 HDL2 and 6 control cases. The quality of the tissues was assessed to minimize variability due to post mortem autolysis. We applied a robust median sweep algorithm to quantify protein abundance and performed statistical inference using moderated test statistics. 1211 proteins showed statistically significant fold changes between HD and control tissues; the differences in selected proteins were verified by Western blotting. Differentially abundant proteins were enriched in cellular pathways previously implicated in HD, including Rho-mediated, actin cytoskeleton and integrin signaling, mitochondrial dysfunction, endocytosis, axonal guidance, DNA/RNA processing, and protein transport. The abundance of 717 proteins significantly differed between control and HDL2 brain. Comparative analysis of the disease-associated changes in the HD and HDL2 proteomes revealed that similar pathways were altered, suggesting the commonality of pathogenesis between the two disorders.
KW - Huntington's disease
KW - TMT
KW - human brain
KW - iTRAQ
KW - neurodegenerative disorder
KW - proteomics
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U2 - 10.1021/acs.jproteome.6b00448
DO - 10.1021/acs.jproteome.6b00448
M3 - Article
C2 - 27486686
AN - SCOPUS:84985905933
SN - 1535-3893
VL - 15
SP - 3266
EP - 3283
JO - Journal of Proteome Research
JF - Journal of Proteome Research
IS - 9
ER -