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

Abstract

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. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: autophagy; glycosphingolipid; lipid storage diseases; lysosomes; multilamellar bodies; neurodegeneration.

FIG. 1

Impaired brain cholesterol trafficking induced by β‐glucocerebrosidase (GCase) deficiency. Cholesterol is primarily synthesized in astrocytes. (1) Under high cholesterol conditions, astrocytes express specific lipid transporter proteins on their membranes (ATP‐binding cassette transporter protein A1 [ABCA1]) and apolipoprotein E (ApoE) to decrease cholesterol content. In addition, sterol‐regulatory element‐binding protein (SREBP) binds to SREBP cleavage activating protein (SCAP), and both are retained in the endoplasmic reticulum (ER) bound to insulin induced gene (INSIG) to inhibit cholesterol synthesis. When cholesterol content decreases, SREBP‐SCAP is transported to the GA, where SREBP is cleaved. Then SREBP is translocated to the nucleus to activate genes required for its synthesis (3‐hydroxy‐3‐methyglutaryl‐coenzyme‐A reductase [HMGR]) and uptake (low‐density lipoprotein receptor [LDLR]) through its binding to sterol‐regulatory element‐1 (SRE‐1). HMGR can be degraded by proteasome when ER‐cholesterol is accumulated. (2) Synthesized cholesterol binds ApoE, forming an ApoE–cholesterol complex that exits the astrocyte via ABCA1, and it is internalized into the neuron by LDLR and LDLR‐related protein 1. (3) In neurons, LDLR complexes are hydrolyzed, and free cholesterol is disseminated among the plasma membrane and other organelles. (4) The excess of neuronal cholesterol is modulated by cholesterol esterification through ACAT (acetyl‐coenzyme A acetyltransferase 1) enzyme and storage in lipid droplets that are secreted through the ABCA1. (5) In the ER, the excess cholesterol is converted into 24S‐hydroxycholesterol (24‐OHC). In astrocytes, 24‐OHC and other oxysterols (such as 27‐OHC) bind LXR(Liver X Receptor) to induce the expression of APOE and ABCA1 genes. Moreover, 24‐OHC can cross the BBB. (6) ApoE–cholesterol complex from astrocyte could bind to Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), Toll‐Like Receptor 4 (TLR4), and LDLR on the inflammaraft of the microglia surface to trigger inflammation and phagocytosis. (7) Oxysterols (24‐OCH and 27‐OCH) can bind LXRs to activate microglia. (8) In a pathological state of GBA1‐PD or GCase deficiency, we proposed that cholesterol is accumulating in the lysosomes independently of the cell type. (9) Cholesterol could disturb the interaction between GCase1 and its transporter (LIMP‐2) impairing GCase activity, and it also might disrupt the contact between GCase and its coactivator SapC, favoring lysosomal cholesterol buildup. (10) Cholesterol accumulation appears to lead to lysosome degeneration called multilamellar bodies (MLBs). (11) Lysosomal cholesterol accumulation could affect cholesterol pools in the rest of membrane organelles, which in turn could alter the α‐synuclein (α‐Syn) interaction with lipid rafts and contribute to α‐Syn oligomerization. Ultimately, these α‐Syn oligomers cannot be degraded by lysosomes; as a consequence, they lead to α‐Syn fibrils. (12) The α‐Syn overburden appears to affect GA tubulation and fragmentation. (13) Aberrant α‐Syn is released from neurons and transferred to microglia and astrocytes, and triggers the inflammatory response. (14) We hypothesized that GBA1 mutations increase interleukins and NLRP3 inflammasome activating the inflammatory response. Peroxisome Proliferator‐Activated Receptor (PPAR); Retinoid X Receptor (RXR); Peroxisome Proliferator Response Elements (PPRE); Liver X Receptor Response Elements (LXRE).

FIG. 2

A schematic model illustrating the potential α‐synuclein (α‐Syn) interaction with lipid rafts through cholesterol in PD. Lipid rafts are enriched in cholesterol and other membrane glycolipids, such as sphingolipids. (A) Under physiological conditions, the extracellular domain (blue) of α‐Syn harbors polar amino acid residues that allow its interaction with lipid raft gangliosides, such as ganglioside 1 (GM1) expressed by neurons or GM3 expressed by astrocytes. Thus, GMs allow the attachment of α‐Syn to the surface of plasma membrane (step 2). Then α‐Syn is transferred through the membrane by forming a complex with cholesterol and its tilted peptide domain (green) (step 1). ⁸⁸ , ⁸⁹ (B) In the pathological state of GBA1‐PD or β‐glucocerebrosidase (GCase) deficiency, we proposed that cholesterol accumulation in the lysosomes could affect cholesterol levels in the lipid raft that in turn alter α‐Syn interactions with cholesterol. Ultimately, this alteration could favor α‐Syn oligomerization inside the cells or in the synaptic membrane, contributing to PD pathology. Noticeably, gangliosides content in lipid raft is increased in PD. ⁹⁰

FIG. 3

Transneuronal propagation of pathogenic α‐synuclein (α‐Syn) through multilamellar bodies (MLBs) in Parkinson's disease (PD). First, a schematic illustration representing the role of intracellular cholesterol trafficking in hypothetical MLB biogenesis is zoom visualized. The MLB biogenesis, a pathological type of lamellar body found in GBA1‐PD fibroblasts, is completely unknown. We hypothesize that Rab11a and ABCA‐like transporters could be involved. ABCA3 could ingress cholesterol or other lipids from other donor organelles into MLB for its biogenesis and, in turn, from MLBs into the endosomes. Overall, ABCA3 play a critical role in the maturation of the multivesicular bodies (MVBs) into the MLBs through fusion with the autophagolysosome by helping these vesicles become filled with lipids and cholesterol. Second, a diagram illustrates how GBA1 mutations alter the dynamics of autophagosome–lysosomes and endosomes. Accumulating cholesterol generates MVBs and MLBs containing pathogenic α‐Syn that could degenerate into Lewy bodies (LBs). Multilamellar (ML) or multivesicular (MV) organelles, as well as naked α‐Syn, could be secreted from dying neurons (blue) and, in turn, captured by healthy neurons (pink) or glial cells (yellow and orange) propagating α‐Syn pathology. Once inside the healthy neuron, α‐Syn fibrils break the ML membrane to reach the cytosol, where they seed new aggregates by recruiting monomeric α‐Syn. Notably, GCase lysosomal dysfunction increases the amount of MV endosomes that secrete α‐Syn by exosomes. Bottom right panel shows the α‐Syn aggregation process.