Serrano Fernandez, Pablo, Kaiser, Sergio, Zhang, Luqing, Dovlatyan, Mary, Sanz, Vinicius, Li, Jingyao, Kostikova, Anna, Rotte, Michael and Messa, Mirko (2023) Parkinson’s disease causality and heterogeneity: a proteogenomic view. NPJ parkinson's disease, 9 (1). p. 24. ISSN 23738057

Abstract

The pathogenesis and clinical heterogeneity of Parkinson’s disease have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of CSF has opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in Parkinson’s disease with 569 patients (350 idiopathic patients, 65 GBA+ mutation carriers and 154 LRRK2+ mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest Parkinson’s disease genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB was previously reported to be upregulated in the substantia nigra of Parkinson’s disease patients.
We also compared the CSF proteomes of patients and controls. The Parkinson’s disease cohort comprised not only LRRK2+ and GBA+ mutation carriers but also idiopathic patients. Proteome differences between GBA+ patients and unaffected GBA+ controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. The proteins discriminating LRRK2+ patients from unaffected LRRK2+ controls, revealed dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction / oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances.
Finally, we used proteomic data to stratify idiopathic patients into "endotypes". The identified endotypes show differences in cognitive and motor disease progression based on the use of previously reported protein-based risk scores.
In summary, we: i) identified causal proteins for Parkinson’s disease, ii) assessed CSF proteome differences in Parkinson’s disease patients of genetic and idiopathic etiology, and. iii) stratified idiopathic patients into robust clinically relevant subtypes. Our findings not only contribute to the identification of new therapeutic targets but also to shaping personalized medicine in CNS neurodegeneration.

Item Type:	Article
Keywords:	Parkinson’s Disease, GBA, LRRK2, SomaScan, proteomics, CSF, personalized Medicine, stratification, network analysis, cluster, endotype, causal analysis, mendelian randomization, pQTL, GWAS
Date Deposited:	14 Mar 2023 00:45
Last Modified:	14 Mar 2023 00:45
URI:	https://oak.novartis.com/id/eprint/48650