Lipids as Trans-Acting Effectors for α-Synuclein in the Pathogenesis of Parkinson’s Disease

Kensuke Ikenaka,Yoshitaka Nagai,Mari Suzuki,Hideki Mochizuki

doi:10.3389/fnins.2019.00693

Kensuke Ikenaka, Yoshitaka Nagai + Show 2 more

Open Access

https://doi.org/10.3389/fnins.2019.00693

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Abstract

Aggregation of α-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Lewy bodies (LBs) and Lewy neurites, which consist mainly of aggregated αSyn, are widely observed in the affected regions of patient brains. Except for some familial forms of PD/DLB, most sporadic PD/DLB patients express the wild-type (WT) αSyn protein without any mutations, and the mechanisms as to how WT αSyn gains the propensity to pathologically aggregate still remains unclear. Furthermore, the mechanisms by which the same αSyn protein can cause different synucleinopathies with distinct phenotypes and pathologies, such as PD, DLB, and multiple system atrophy (MSA), still remain largely unknown. Recently, mutations in the GBA1 gene (encoding glucocerebrosidase), which are responsible for the lysosomal storage disorder Gaucher disease (GD), have been reported to be the strongest risk factor for developing sporadic PD/DLB. We previously demonstrated that glucosylceramide accumulated by GBA1 deficiency promotes the conversion of αSyn into a proteinase K-resistant conformation. Furthermore, decreased glucocerebrosidase activity has also been reported in the brains of patients with sporadic PD/DLB. Moreover, αSyn pathology has also been shown in the brains of lysosomal storage disorder patients, which show glycosphingolipid accumulation. These observations suggest the possibility that altered lipid metabolism and lipid accumulation play roles in αSyn aggregation and PD/DLB pathogenesis. Indeed, several previous studies have demonstrated that lipid interactions affect the conformation of αSyn and induces its oligomerization and aggregation. In this review, we will give an overview of the association between αSyn aggregation and lipid interactions from the viewpoints of the etiology, pathology, and genetics of PD/DLB. We also discuss the distinct species of αSyn aggregates and their association with specific types of synucleinopathies, and introduce our hypothesis that lipid interactions play a role as trans-acting effectors in producing distinct strains of αSyn fibrils.

Highlights

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by preferential loss of dopaminergic neurons in the pars compacta of the substantia nigra (Scott and Netsky, 1961)
LBs are widely observed in the cortex and other brain regions of patients with dementia with Lewy bodies (DLB) (Spillantini et al, 1998a), which predominantly exhibits dementia accompanied with frequent visual hallucinations and dopa-responsive Parkinsonism (Burkhardt et al, 1988; Byrne et al, 1989; Klatka et al, 1996)
We propose our hypothesis that lipids interacting with αSyn may work as trans-acting effectors that induce variable conformational changes in the αSyn monomer, into structurally distinct αSyn fibrils, which may lead to clinically distinct synucleinopathies

Summary

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by preferential loss of dopaminergic neurons in the pars compacta of the substantia nigra (Scott and Netsky, 1961). A rare mutation in the GBA1 gene increases the risk of developing PD/DLB, and a decrease in GCase activity has been reported in the biofluid or brains of sporadic PD patients (Balducci et al, 2007; Gegg et al, 2012; Parnetti et al, 2014; Chiasserini et al, 2015; Rocha et al, 2015; Moors et al, 2019).

Results

Conclusion