Parkinson’s disease: proteinopathy or lipidopathy?

Abstract

Lipids play a more significant role in Parkinson’s disease and its related brain disorders than is currently recognized, supporting a “lipid cascade”. The 14 kDa protein α-synuclein (αS) is strongly associated with Parkinson’s disease (PD), dementia with Lewy bodies (DLB), other synucleinopathies such as multiple system atrophy, and even certain forms of Alzheimer’s disease. Rigorously deciphering the biochemistry of αS in native systems is the key to developing treatments. αS is highly expressed in the brain, the second most lipid-rich organ, and has been proposed to be a lipid-binding protein that physiologically interacts with phospholipids and fatty acids (FAs). αS-rich cytoplasmic inclusions called Lewy bodies and Lewy neurites are the hallmark lesions of synucleinopathies. Excess αS–membrane interactions may trigger proteinaceous αS aggregation by stimulating its primary nucleation. However, αS may also exert its toxicity prior to or independent of its self-aggregation, e.g., via excessive membrane interactions, which may be promoted by certain lipids and FAs. A complex αS-lipid landscape exists, which comprises both physiological and pathological states of αS. As novel insights about the composition of Lewy lesions occur, new lipid-related PD drug candidates emerge, and genome-wide association studies (GWAS) increasingly validate new hits in lipid-associated pathways, it seems timely to review our current knowledge of lipids in PD and consider the roles for these pathways in synucleinopathies.Fig. 1αS ↔ lipid interplay: aspects of cellular αS homeostasis (blue oval), aspects of lipid homeostasis (green oval), and overlapping aspects.Pathological states are labeled in red. Simplified schematic of both select αS and select lipid species. Several existing publications suggest αS effects on lipids and vice versa, as indicated by arrows. DG diglyceride, ER endoplasmic reticulum, FA fatty acid, LD, lipid droplet, TG triglyceride.

Lipid Droplets in Neurodegenerative Disorders

“…When looking at these findings together, it is evident that LDs and lipid homeostasis play a more significant role in PD than originally thought. This line of thought is supported by Fanning et al (2020) who stated that α-synuclein toxicity and cell trafficking defects have been associated with aberrations in LD content and distribution. PD has classically been believed to be a "proteinopathy, " but with many of the recent discoveries, lipid dyshomeostasis is rapidly becoming one of the fundamental characteristics of this disease (Fanning et al, 2020).…”

A series of helical α-synuclein fibril polymorphs are populated in the presence of lipid vesicles

“…Here we describe very different and much larger assemblies that have not been previously reported, and which form specifically in the presence of lipid vesicles. This is particularly interesting given the emerging discussion over whether Parkinson's disease (PD) is a proteinopathy or lipidopathy 20 . These newly reported structures are able to be readily viewed using transmission EM (TEM) and range in polymorph from structures that are ribbon like to those that are highly helical and compact, with a range of observed helical assemblies in between.…”

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

“…Lipid dysregulation including lipid droplets dyshomeostasis have been reported to be part of glial cells' stress response during neurodegeneration processes 5,7-9 and in the context of PD 39 . Here, we found that SPEN/SHARP belongs to the set of astrocyteexpressed genes which mRNA levels are significantly different in the substantia nigra of PD patients as compared to controls.…”