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

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 ?-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 ?-synuclein, in addition to seeing a reduction of CHCHD2 in erythrocytes of the same animals. Overexpression of ?-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.

SUBMITTER: Liu X

PROVIDER: S-EPMC7941904 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Liu Xiaodan X Wang Qilong Q Yang Ying Y Stewart Tessandra T Shi Min M Soltys David D Liu Genliang G Thorland Eric E Cilento Eugene M EM Hou Yiran Y Liu Zongran Z Feng Tao T Zhang Jing J

Acta neuropathologica communications 20210308 1

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 sign ...[more]

PMID: 33685516

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Project description:Parkinson's disease is delayed in clinical onset, asymmetric in initial appearance, and slow in progression. One explanation for these characteristics may be a boost in natural defenses after early exposure to mild cellular stress. As the patient ages and resilience recedes, however, stress levels may become sufficiently high that toxic cellular responses can no longer be curbed, culminating in inverted U-shaped stress-response curves as a function of disease duration. If dopaminergic systems are indeed capable of responding to mild stress with effective natural defenses, experimental models of Parkinson's disease should adhere to the principles of preconditioning, whereby stress exposure fortifies cells and tempers the toxic sequelae of subsequent stressors. Here, I review evidence favoring the efficacy of preconditioning in dopaminergic systems. Recent animal work also raises the possibility that cross-hemispheric preconditioning may arrest the spread of asymmetric Parkinson's pathology to the other side of the brain. Indeed, compensatory homeostatic systems have long been hypothesized to maintain neurological function until a threshold of cell loss is exceeded and are often displayed as inverted U-shaped curves. However, some stress responses assume an exponential or sigmoidal profile as a function of disease severity, suggesting end-stage deceleration of disease processes. Thus, surviving dopaminergic neurons may become progressively harder to kill, with the dorsal nigral tier dying slower due to superior baseline defenses, inducible conditioning capacity, or delayed dorsomedial nigral spread of disease. In addition, compensatory processes may be useful as biomarkers to distinguish "responder patients" from "nonresponders" before clinical trials. However, another possibility is that defenses are already maximally conditioned in most patients and no further boost is possible. A third alternative is that genuinely diseased human cells cannot be conditioned, in contrast to preclinical models, none of which faithfully recapitulate age-related human conditions. Disease-related "conditioning deficiencies" would then explain how Parkinson's pathology takes root, progressively shrinks defenses, and eventually kills the patient.

Dataset Information

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

Publications

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

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