Integrated molecular landscape of Parkinson’s disease

Abstract

Parkinson’s disease is caused by a complex interplay of genetic and environmental factors. Although a number of independent molecular pathways and processes have been associated with familial Parkinson’s disease, a common mechanism underlying especially sporadic Parkinson’s disease is still largely unknown. In order to gain further insight into the etiology of Parkinson’s disease, we here conducted genetic network and literature analyses to integrate the top-ranked findings from thirteen published genome-wide association studies of Parkinson’s disease (involving 13.094 cases and 47.148 controls) and other genes implicated in (familial) Parkinson’s disease, into a molecular interaction landscape. The molecular Parkinson’s disease landscape harbors four main biological processes—oxidative stress response, endosomal-lysosomal functioning, endoplasmic reticulum stress response, and immune response activation—that interact with each other and regulate dopaminergic neuron function and death, the pathological hallmark of Parkinson’s disease. Interestingly, lipids and lipoproteins are functionally involved in and influenced by all these processes, and affect dopaminergic neuron-specific signaling cascades. Furthermore, we validate the Parkinson’s disease -lipid relationship by genome-wide association studies data-based polygenic risk score analyses that indicate a shared genetic risk between lipid/lipoprotein traits and Parkinson’s disease. Taken together, our findings provide novel insights into the molecular pathways underlying the etiology of (sporadic) Parkinson’s disease and highlight a key role for lipids and lipoproteins in Parkinson’s disease pathogenesis, providing important clues for the development of disease-modifying treatments of Parkinson’s disease.

Split-ends is modulating lipid droplet content in adultDrosophilaglial cells and is protective against paraquat toxicity

“…Indeed, using a data mining approach, we found that genes previously shown to exhibit an altered expression profile in the substantia nigra of PD are not only enriched in astrocyte-expressed genes such as SPEN/SHARP but also include a significant number of genes annotated with the GO terms "phospholipid metabolism", "lipid and lipoprotein metabolism" or "sphingolipid metabolism" (Table 1). These results pointing to a pathophysiological role of lipid metabolism in PD are in accordance with a previous data mining work based on the meta-analysis of GWAS (genome-wide association studies) studies 43 . Importantly, we found that several lipid-related genes, which are differentially expressed in the substantia nigra of PD patients, are likely involved in the regulation of lipid droplets formation and fate.…”

Genetic risk factors in Parkinson’s disease

“…A recent study constructed a PD protein network from risk loci and identified over 500 candidate genes that could be implicated in the condition from the GWAS hits (Klemann et al 2017). With identification of many more risk loci anticipated and the costly and time-intensive nature of dissecting risk loci, there is a focus on developing methods to more accurately determine the correct genes to pursue for further research, in order to unpin the molecular basis of PD.…”

Understanding the Links Between Cardiovascular Disease and Parkinson's Disease

“…Yet although the ε2 allele is linked to a number of beneficial outcomes in terms of CV disease and a lower risk of Alzheimer's disease, some studies, but not all, have associated it with a higher risk of PD, whereas the more common ε4 allele is associated with poorer CV disease outcomes and a significantly increased risk of Alzheimer's disease, but is associated with lower PD risk . There are fascinating mechanisms that may be relevant, for example, a large clinical study provided evidence that lipids and lipoproteins may affect dopamine neuron–specific signaling cascades . Other studies show that cholesterol recycling may be linked to PD, and related genes are associated with increased PD risk or are affected in animal models of PD or PD itself …”

“…114 There are fascinating mechanisms that may be relevant, for example, a large clinical study provided evidence that lipids and lipoproteins may affect dopamine neuron-specific signaling cascades. 115 Other studies show that cholesterol recycling may be linked to PD, 109,110,114 and related genes are associated with increased PD risk 116 or are affected in animal models of PD 117 or PD itself. 118 Despite the literature linking serum/plasma total and LDL cholesterol to PD, 26,27,30,40,47,[96][97][98][99][100][101][102] the cause of the association is not known and further complicated by the compartmentalization of the brain and peripheral cholesterol.…”