LRRK2 and Lipid Pathways: Implications for Parkinson's Disease

Abstract

Genetic alterations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson's disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in lipid pathways. It is increasingly recognized that in addition to being energy reservoirs and structural entities, some lipids, including neural lipids, participate in signaling cascades. Early investigations revealed that LRRK2 localized to membranous and vesicular structures, suggesting an interaction of LRRK2 and lipids or lipid-associated proteins. LRRK2 substrates from the Rab GTPase family play a critical role in vesicle trafficking, lipid metabolism and lipid storage, all processes which rely on lipid dynamics. In addition, LRRK2 is associated with the phosphorylation and activity of enzymes that catabolize plasma membrane and lysosomal lipids. Furthermore, LRRK2 knockout studies have revealed that blood, brain and urine exhibit lipid level changes, including alterations to sterols, sphingolipids and phospholipids, respectively. In human LRRK2 mutation carriers, changes to sterols, sphingolipids, phospholipids, fatty acyls and glycerolipids are reported in multiple tissues. This review summarizes the evidence regarding associations between LRRK2 and lipids, and the functional consequences of LRRK2-associated lipid changes are discussed.

Keywords: BMP; LRRK2; Parkinson’s disease; ceramide; cholesterol; glucocerebrosidase; glucose; lipid; lysosome; metabolism.

Figure 2

Lipid level changes in tissues from LRRK2 mutation carrier humans and LRRK2^-/- rodents. Human LRRK2 G2019S mutation carriers have alterations in serum phospholipid, sphingolipid and glycerolipid species, and CSF sphingolipid and glycerolipid species compared to those without a LRRK2 mutation [26]. Human LRRK2 G2019S mutation carriers have increased BMP and PI species in urine compared to those without the mutation [24]. Human LRRK2 R1441G mutation carriers have decreased plasma cholesterol [22]. LRRK2^-/- rats have higher serum [15] and plasma [16] cholesterol, and lower serum triacylglycerol [15] compared to WT. LRRK2^-/- mice have increased brain ceramide [13] and decreased urine BMP [14] compared to WT. For simplicity, specific lipid species are not depicted (detailed lipid species information is included in Section 1.3 and Section 1.4). Hex1Cer = hexosylceramide, Cer = ceramide, DG = diacylglycerol, BMP = bis (monoacylglycerol) phosphate, PI = phosphatidylinositol, PC = phosphatidylcholine, SM = sphingomyelin, PE = phosphatidylethanolamine, MGDG = monogalactosyldiacylglycerol, TG = triacylglycerol, LPC = lysophosphatidylcholine, Chol = cholesterol. Created with BioRender.com (accessed on 26 October 2022).

Figure 1

Top panel: Lipid categories and examples of their cellular location. Bottom panel: Enzymatic and chemical assays can measure total lipid levels, while mass spectrometry techniques can discern the levels of specific lipid species, which have varying degrees of unsaturation and carbon chain lengths. Created with BioRender.com (accessed on 26 October 2022).

Figure 3

Summary of LRRK2 functions which impact lipids. Solid grey arrows represent direct phosphorylation by LRRK2 and dashed grey lines indicate a possible indirect or direct effect by LRRK2 through an unresolved mechanism of action. Synaptojanin-1 is a putative LRRK2 substrate that dephosphorylates phospholipid at the cell membrane, which is important for synaptic vesicle recycling and also insertion of GLUT-1 in the plasma membrane. Rab proteins phosphorylated by LRRK2 are also involved in recycling membrane receptors such as GLUT-4. Rabs are also involved in the trafficking of synaptic vesicles in vesicle recycling or degradation pathways. In addition, Rabs are involved in lipid droplet fusion, autophagy and transport of lipids from droplets to the cell membrane. Lipid droplets are also a reservoir for substrates important for mitochondrial oxidative phosphorylation. LRRK2 affects the endolysosomal lipid BMP, which in turn appears to affect endolysosomal cholesterol levels. LRRK2 may also have an effect on GCase activity and the levels of GCase substrates and metabolites. PI(4,5)P₂ = phosphatidylinositol 4,5-bisphosphate, PI = phosphatidylinositol, Chol = cholesterol, BMP = bis(monoacylglycerol) phosphate, GluCer = glucosylceramide, Cer = ceramide, GalCer = galactosylceramide, Sph = sphingosine, GluSph = glucosylsphingosine, SV = synaptic vesicle, LPC = lysophosphatidylcholine, DG = diacylglycerol, PA = phosphatidic acid, FA = fatty acid, AcCa = acylcarnitine, phos = phosphorylation. Created with BioRender.com (accessed on 26 October 2022).