Explorative Combined Lipid and Transcriptomic Profiling of Substantia Nigra and Putamen in Parkinson's Disease.

Helena Xicoy,Jos F Brouwers,Bé Wieringa,Gerard J M Martens

doi:10.3390/cells9091966

Abstract

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons from the substantia nigra (SN) that project to the dorsal striatum (caudate-putamen). To better understand the molecular mechanisms underlying PD, we performed combined lipid profiling and RNA sequencing of SN and putamen samples from PD patients and age-matched controls. SN lipid analysis pointed to a neuroinflammatory component and included elevated levels of the endosomal lipid Bis (Monoacylglycero)Phosphate 42:8, while two of the three depleted putamen lipids were saturated sphingomyelin species. Remarkably, we observed gender-related differences in the SN and putamen lipid profiles. Transcriptome analysis revealed that the top-enriched pathways among the 354 differentially expressed genes (DEGs) in the SN were “protein folding” and “neurotransmitter transport”, and among the 261 DEGs from putamen “synapse organization”. Furthermore, we identified pathways, e.g., “glutamate signaling”, and genes, encoding, e.g., an angiotensin receptor subtype or a proprotein convertase, that have not been previously linked to PD. The identification of 33 genes that were common among the SN and putamen DEGs, which included the α-synuclein paralog β-synuclein, may contribute to the understanding of general PD mechanisms. Thus, our proof-of-concept data highlights new genes, pathways and lipids that have not been explored before in the context of PD.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease
The lipid compositions of the substantia nigra (SN) and putamen samples from PD patients and controls were analyzed by LC–MS
We identified 269 phospholipids of the following classes: Bis (Monoacylglycero)Phosphate (BMP), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI) and phosphatidylserine (PS), and the sphingolipid sphingomyelin (SM; Spreadsheet S1)

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease. PD is rare in individuals less than 50 years old, but its prevalence increases with age, reaching up to 4% in older-age groups [1]. Lewy bodies (abnormal intracellular aggregates containing metals, lipids and proteins like α-synuclein), a progressive loss of dopaminergic neurons that project from the substantia nigra (SN) to the dorsal part of the striatum (which consists of the caudate nucleus and putamen), and microgliosis [4]. Current knowledge of the molecular mechanisms underlying these pathological hallmarks has been derived from studies on 27 monogenic familial forms of PD [5], which represent only 5–10%. The most salient mechanisms described up to now include mitochondrial dysfunction and oxidative stress, unfolded protein response, protein aggregation, lysosomal dysfunction and neuroinflammation [10]. The existing data has not resulted in the development of disease-modifying treatments for PD

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Conclusion