The Role of Cholesterol in α‐Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease

Abstract

A BS TRACT: Parkinson's disease (PD) is a progressive neurodegenerative disease where dopaminergic neurons in the substantia nigra are lost, resulting in a decrease in striatal dopamine and, consequently, motor control. Dopaminergic degeneration is associated with the appearance of Lewy bodies, which contain membrane structures and proteins, including α-synuclein (α-Syn), in surviving neurons. PD displays a multifactorial pathology and develops from interactions between multiple elements, such as age, environmental conditions, and genetics. Mutations in the GBA1 gene represent one of the major genetic risk factors for PD. This gene encodes an essential lysosomal enzyme called β-glucocerebrosidase (GCase), which is responsible for degrading the glycolipid glucocerebroside into glucose and ceramide. GCase can generate glucosylated cholesterol via transglucosylation and can also degrade the sterol glucoside. Although the molecular mechanisms that predispose an individual to neurodegeneration remain unknown, the role of cholesterol in PD pathology deserves consideration. Disturbed cellular cholesterol metabolism, as reflected by accumulation of lysosomal cholesterol in GBA1-associated PD cellular models, could contribute to changes in lipid rafts, which are necessary for synaptic localization and vesicle cycling and modulation of synaptic integrity. α-Syn has been implicated in the regulation of neuronal cholesterol, and cholesterol facilitates interactions between α-Syn oligomers. In this review, we integrate the results of previous studies and describe the cholesterol landscape in cellular homeostasis and neuronal function. We discuss its implication in α-Syn and Lewy body pathophysiological mechanisms underlying PD, focusing on the role of GCase and cholesterol.

Bioactive lipids and their metabolism: New therapeutic opportunities for Parkinson's disease

“…The human brain is composed of 25% cholesterol, and its dysregulation caused by oxidative stress and/or inflammation can further contribute to α‐synuclein trafficking, leading to PD progression (Pingale & Gupta, 2021). Recently, the cell experiments performed by García‐Sanz et al (2018, 2021) proposed that the accumulation of cholesterol in the lysosomes caused by a mutation in GBA1 (the gene encoding glucocerebrosidase)‐induced PD or glucocerebrosidase deficiency might indirectly increase the levels of α‐synuclein by compromising lysosomal activity and altering cholesterol levels in the lipid raft.…”

Exploring the Role of Lipid-Binding Proteins and Oxidative Stress in Neurodegenerative Disorders: A Focus on the Neuroprotective Effects of Nutraceutical Supplementation and Physical Exercise

“…Indeed, 24S-OHC is able to protect neurons from the cytotoxicity of 7-ketocholesterol, inducing their adaptations, as well as reducing Aβ accumulation and tau hyperphosphorylation. On the other hand, the same molecule seems to induce cell apoptosis favoring the activity of caspase proteins, leading to the formation of abnormal lipid structures, and increasing oxidative stress [ 110 , 111 , 112 , 113 , 114 ].…”

“…Cholesterol metabolism also seems to be involved in PD pathogenesis: cholesterol excess in lysosomes leads to abnormalities in the lipid rafts, which are membrane microdomains enriched in cholesterol and sphingolipids [ 111 ]. As a consequence, altered interactions between cholesterol and α-syn occur in brain cells, enhancing α-syn oligomerization and thus influencing PD pathogenesis [ 112 ]. Causes of this excess of cholesterol inside lysosomes could be mutations that occur in the GBA1 gene that encodes for the lysosomal enzyme β-glucocerebrosidase-1 and are shown to correlate with PD.…”

Lower Blood Lipid Level Is Associated with the Occurrence of Parkinson’s Disease: A Meta-Analysis and Systematic Review

“…Therefore, searching for biomarkers related to the risk and severity of PD has become a hot spot in clinical research in recent years. In recent years, blood lipids have become a blood biochemical index that may be related to PD in many clinical studies [ 41 , 42 ], but the results of the studies are not consistent. The results of our synthesized outcomes have indicated that the TC, TG, HDL-C, and LDL-C level in the PD patients was significantly lower than that of health controls.…”