Identifying genetic targets in clinical subtypes of Parkinson's disease for optimizing pharmacological treatment strategies

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.

Fig. 1

Establishment of the rat model for different PD subtypes. a The schematic diagram of the experimental protocols. b Rotational behavior test. c Athletic ability evaluation including rotarod test, neurological function test and open field test. d electromyography (EMG) for tremor monitor. e Body weight. f Behavioral data of different subtypes of PD rats for classification. g Segments of tremor monitor activity profiles. h The movement routes. i, k Representative images and quantitative analysis of TH immunohistochemical staining in normal and lesioned SN of rats. j, l Representative images and quantitative analysis of α-syn immunofluorescence staining in lesioned SN of rats. m, n NfL and UA concentration in serum. The data described are Mean ± SEM, n = 5–132. *p < 0.05, **p < 0.01 and ***p < 0.001 vs. control; ^#p < 0.05, ^##p < 0.01 and ^###p < 0.001 vs. other subtype

Fig. 2

Metabolomic analysis and transcriptomic analysis of rats and patients with different subtypes of PD. a, b Volcano plots of metabolites detected in the serum of rats and clinical patients. c The number of metabolites with consistent or inconsistent changes in rats and clinical patients serum. d Differences of gene expression in Volcano plot and the intersection of DEGs related to PD. e KEGG pathways about neurological disorders. n = 3–6

Fig. 3

Subtypes of PD differ for neuronal development and differentiation. The biological function of neuronal development and differentiation in Mix (a), TD (b) and PIGD (c) subtypes of PD rats. d–h Relative mRNA levels of Itgb4, Drx, Ncmap, Cldn1, Myoc, Dbh, Foxp2, Gbx2, Isl1, Gabrb1, Wnt2, Lmx1a and Wnt9b detected by RT-PCR. Data described are Mean ± SEM, n = 3-6. *p < 0.05, **p < 0.01 and ***p < 0.001 vs. control. ^#p < 0.05, ^##p < 0.01 and ^###p < 0.001 vs. other subtype

Fig. 4

Analysis of neurotransmitter anabolic pathway and fatty acids in different subtypes of PD rats. a, e The biological function of neurotransmitter and dopamine in different subtype of PD rats. b–d 5-HT, GABA and DA concentration in SN. f The biological function of lipid and fatty in Mix, TD, and PIGD subtypes of PD rats. Data described are Mean ± SEM, n = 3-6. *p < 0.05, **p < 0.01 and ***p < 0.001 vs. control, ^#p < 0.05 vs. other subtype

Fig. 5

Potential therapeutic effects of PD treatment candidates on subtypes. a The flowchart illustrating the sequential steps involved in the search and selection process used in systematic data retrieval. b–d PPI network of Mix (b), TD (c) and PIGD (d) subtypes. e–l Relative mRNA levels of A2m, Chrnb4, Grm2, Rgs4, Slc7a11, VDR, Alox15, Slc18a2, Aldh1a1, Drd2, Fkbp5, Kcnj6, Nfbkia and Nr4a1 detected by RT-PCR. Data described are Mean ± SEM, n = 3–7. *p < 0.05, **p < 0.01 and ***p < 0.001 vs. control, ^#p < 0.05 vs. other subtype

Fig. 6

Effectiveness of baicalein (Bai) and madopar (Mad) on different PD subtypes of rats. a Rotarod test. b Neurological function test. c Open field test. d Electromyography. e The movement routes. f Segments of tremor monitor activity profiles. g Representative images of TH immunohistochemical staining in SN of rats. h–j Representative image of TH, Alox15 expression in the lesioned SN. Data described are Mean ± SEM, n = 3-12. *p < 0.05, **p < 0.01 and ***p < 0.001 vs. control, ^#p < 0.05, ^##p < 0.01 and ^###p < 0.001 vs. other subtype