Identifying Genetic Targets in Clinical Subtypes of Parkinson's Disease for Optimizing Pharmacological Treatment Strategies

Overview

Journal Signal Transduct Target Ther

Specialties Cell Biology
Pharmacology

Date 2024 Nov 17

PMID 39551798

Authors

Dewen Kong

Cao Li

Lingyan Ma

Lida Du

Nan Jiang

Xiaoyue Zhao

Sen Zhang

Zhigang Zhao

Lianhua Fang

Guanhua Du

Affiliations

Soon will be listed here.

Abstract

The heterogeneity of Parkinson's disease (PD) has been recognized in clinical, with patients categorized into distinct subsets based on motor phenotype, such as tremor-dominant PD (TD), postural instability and gait difficulty-dominant PD (PIGD) and mixed PD (Mix). Despite this categorization, the underlying mechanisms of this heterogeneity remain poorly understood, and there is no personalized effective treatment for each PD subtype. To address this, a rat model for PD subtypes was established by unilateral stereotaxic injection of 6-OHDA, followed by cluster analysis of behavioral data. The serum neurofilament light chain (NfL) and uric acid (UA) levels as well as alterations in brain autonomic activity in rats were consistent with clinical patients, and metabolomics results showed that more than 70% of the metabolites in the serum of different subtypes of PD rats and clinical patients appeared to be consistently altered. Further transcriptomic analysis by RNA-seq has elucidated that the development of PD subtypes is associated with altered gene expression in neurotransmitter, neuronal damage in the central or peripheral nervous system, and lipid metabolism. In addition, based on the subtype-specific differentially expressed genes, 25 potential drug candidates were identified. Notably, the Alox15 inhibitor baicalein showed a greater efficacy on Mix rats, highlighting the possibility of selecting targeted treatments for well-defined individuals.

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