Reduced erythrocytic CHCHD2 mRNA is associated with brain pathology of Parkinson's disease.

Affiliation

Liu X(#)(1)(2), Wang Q(#)(1), Yang Y(#)(1), Stewart T(3), Shi M(3), Soltys D(3), Liu G(4)(5), Thorland E(3), Cilento EM(3), Hou Y(6), Liu Z(1), Feng T(7)(8)(9), Zhang J(10)(11)(12).
Author information:
(1)Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China.
(2)Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China.
(3)Department of Pathology, School of Medicine, University of Washington, Seattle, WA, USA.
(4)Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
(5)China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China.
(6)The Affiliated High School of Peking University, Beijing, 100080, China.
(7)Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China. [Email]
(8)China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China. [Email]
(9)Parkinson's Disease Center, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100069, China. [Email]
(10)Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China. [Email]
(11)Department of Pathology, The First Affiliated Hospital and School of Medicine, Zhejiang University, Hangzhou, China. [Email]
(12)China National Health and Disease Human Brain Tissue Resource Center, Hangzhou, China. [Email]
(#)Contributed equally

Abstract

Peripheral biomarkers indicative of brain pathology are critically needed for early detection of Parkinson's disease (PD). In this study, using NanoString and digital PCR technologies, we began by screening for alterations in genes associated with PD or atypical Parkinsonism in erythrocytes of PD patients, in which PD-related changes have been reported, and which contain ~ 99% of blood α-synuclein. Erythrocytic CHCHD2 mRNA was significantly reduced even at the early stages of the disease. A significant reduction in protein and/or mRNA expression of CHCHD2 was confirmed in PD brains collected at autopsy as well as in the brains of a PD animal model overexpressing α-synuclein, in addition to seeing a reduction of CHCHD2 in erythrocytes of the same animals. Overexpression of α-synuclein in cellular models of PD also resulted in reduced CHCHD2, via mechanisms likely involving altered subcellular localization of p300 histone acetyltransferase. Finally, the utility of reduced CHCHD2 mRNA as a biomarker for detecting PD, including early-stage PD, was validated in a larger cohort of 205 PD patients and 135 normal controls, with a receiver operating characteristic analysis demonstrating > 80% sensitivity and specificity.