There’s no shortage of genes associated with Parkinson’s disease.

Known mutations in 6 genes can cause early onset or classical, late onset Parkinson’s disease, and mutations in at least 2 more can cause atypical parkinsonian syndromes.¹ Additional genetic loci and identified genes increase the susceptibility to Parkinson’s disease.

Although the identified genes are not all part of the same biological pathway, identifying commonalities among them may provide clues to the disease process.  One theme that emerges from these studies is the involvement of lipids.² Investigators have identified links between Parkinson’s disease and lipids for at least 20 years.³ Lipids are integral to biological membranes, such as those that encase nerve cells and cellular organelles, and are a major component of gangliosides, a type of glycolipid concentrated in plasma membranes that participates in cell-cell recognition, adhesion, and signal transduction.⁴ Below is a list of genes associated with Parkinson’s disease that encode proteins with lipid-related functions.

• SNCA: Mutations, duplications, or triplications of the SNCA gene cause an aberration in alpha synuclein amino acid sequence or an overproduction of the protein. Alpha synuclein interacts with the lipid bilayers of membranes, which can trigger protein misfolding.⁵
• LRRK2: Leucine rich repeat kinase protein regulates many different vesicular trafficking pathways by binding to vesicle membranes.⁶
• GBA: The GBA gene encodes glucocerebrosidase, a lysosomal enzyme that cleaves glucocerebroside into glucose and ceramide. Glucocerebroside (also called glucosylceramide) is the precursor to nearly all gangliosides in the brain.⁷
• PLA2G6: PLA2G6 abnormalities have been linked to neuroaxonal dystrophy or early-onset dystonia parkinsonism.¹ This gene encodes a phospholipase A2 enzyme that metabolizes phospholipids, particularly phosphatidylcholine, thereby helping maintain membrane integrity.⁸
• PARK2: This gene encodes Parkin, an E3 ubiquitin protein ligase that is primarily known for its regulation of protein degradation and mitochondrial trafficking. However, Parkin also modulates systemic fat uptake via ubiquitin ligase-dependent effects,⁹ and human fibroblasts with mutated Parkin exhibit higher levels of gangliosides, phosphatidylinositol, and phosphatidylserine.¹⁰
• PARK7: This gene encodes the protein DJ-1, which is involved in mitochondrial function and oxidative stress responses. However, DJ-1 also appears to modulate lipid raft-dependent endocytosis in astrocytes and neurons, as DJ-1 deficiency decreases expression of the main protein components of lipid rafts.¹¹
• ATP13A2: Mutations in this gene cause an early onset parkinsoniam syndrome. The gene encodes an ATPase localized to the lysosomal membrane that participates in the autophagy–lysosome pathway and helps maintain lysosomal pH.^12,13 However, certain mutations in ATP13A2 also cause neuronal ceroid lipofuscinoses, lysosomal storage diseases associated with increased levels of ceramides (lipids highly concentrated in cell membranes).¹⁰ Some patients with neuronal ceroid lipofuscinoses also show parkinsonism.

This evidence suggests that membrane lipids may be a point of convergence for many genes associated with Parkinson’s disease. However, a number of other genes have not been directly associated with lipids, although they have all been associated with membranes.

• PINK1: This gene encodes PTEN-induced putative kinase 1, a mitochondrial serine/threonine-protein kinase that accumulates on the membrane of damaged mitochondria, undergoes autophosphorylation, and recruits Parkin to ubiquitylate the damaged mitochondria.¹⁴
• MAPT: Certain mutations in the MAPT gene may alter susceptibility to Parkinson’s disease.¹⁵ MAPT encodes microtubule associated protein tau, which binds to microtubules and interacts with membranes, which can facilitate its aggregation in vitro.¹⁶
• VPS35: The vacuolar protein sorting gene is a subunit of the retromer, a protein complex involved in recycling membrane proteins.¹⁷

The involvement of all these gene products with membranes (most of which involve lipids) suggests a potential unifying concept. Notably, lipid rafts—transient and variable membrane embedded structures—contain both lipids and proteins.¹⁸ These connections seem to warrant additional consideration. Please leave a comment in the box at the end of this post if you have thoughts or ideas on lipid-Parkinson’s disease connections.

 

 

References

1. Klein C, Westenberger A: Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2(1):a008888. PMC3253033. https://www.ncbi.nlm.nih.gov/pubmed/22315721
2.  Kubo SI: Membrane lipids as therapeutic targets for Parkinson’s disease: a possible link between Lewy pathology and membrane lipids. Expert Opin Ther Targets. 2016;20(11):1301-1310. https://www.ncbi.nlm.nih.gov/pubmed/26610255
3.  Ross BM, Moszczynska A, Erlich J, Kish SJ: Low activity of key phospholipid catabolic and anabolic enzymes in human substantia nigra: possible implications for Parkinson’s disease. Neuroscience. 1998;83(3):791-798. https://www.ncbi.nlm.nih.gov/pubmed/9483562
4.  Yu RK, Tsai YT, Ariga T, Yanagisawa M: Structures, biosynthesis, and functions of gangliosides–an overview. J Oleo Sci. 2011;60(10):537-544. PMC3684167. https://www.ncbi.nlm.nih.gov/pubmed/21937853
5.  Galvagnion C, Buell AK, Meisl G, Michaels TC, Vendruscolo M, Knowles TP, Dobson CM: Lipid vesicles trigger alpha-synuclein aggregation by stimulating primary nucleation. Nat Chem Biol. 2015;11(3):229-234. PMC5019199. https://www.ncbi.nlm.nih.gov/pubmed/25643172
6.  Cookson MR: Cellular functions of LRRK2 implicate vesicular trafficking pathways in Parkinson’s disease. Biochem Soc Trans. 2016;44(6):1603-1610. https://www.ncbi.nlm.nih.gov/pubmed/27913668
7.  Hirabayashi Y: A world of sphingolipids and glycolipids in the brain–novel functions of simple lipids modified with glucose. Proc Jpn Acad Ser B Phys Biol Sci. 2012;88(4):129-143. PMC3406307. https://www.ncbi.nlm.nih.gov/pubmed/22498977
8.  Genetics Home Reference. PLA2G6 gene. phospholipase A2 group VI. https://ghr.nlm.nih.gov/gene/PLA2G6
9.  Kim KY, Stevens MV, Akter MH, Rusk SE, Huang RJ, Cohen A, Noguchi A, Springer D, Bocharov AV, Eggerman TL, Suen DF et al: Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells. J Clin Invest. 2011;121(9):3701-3712. https://www.ncbi.nlm.nih.gov/pubmed/21865652
10.  Lobasso S, Tanzarella P, Vergara D, Maffia M, Cocco T, Corcelli A: Lipid profiling of parkin-mutant human skin fibroblasts. J Cell Physiol. 2017. https://www.ncbi.nlm.nih.gov/pubmed/28109117
11.  Kim JM, Cha SH, Choi YR, Jou I, Joe EH, Park SM: DJ-1 deficiency impairs glutamate uptake into astrocytes via the regulation of flotillin-1 and caveolin-1 expression. Sci Rep. 2016;6(28823. PMC4922019. https://www.ncbi.nlm.nih.gov/pubmed/27346864
12.  Bento CF, Ashkenazi A, Jimenez-Sanchez M, Rubinsztein DC: The Parkinson’s disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway. Nat Commun. 2016;7(11803. PMC4906231. https://www.ncbi.nlm.nih.gov/pubmed/27278822
13.  Yang X, Xu Y: Mutations in the ATP13A2 gene and Parkinsonism: a preliminary review. Biomed Res Int. 2014;2014(371256. PMC4147200. https://www.ncbi.nlm.nih.gov/pubmed/25197640
14.  Okatsu K, Oka T, Iguchi M, Imamura K, Kosako H, Tani N, Kimura M, Go E, Koyano F, Funayama M, Shiba-Fukushima K et al: PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria. Nat Commun. 2012;3(1016. PMC3432468. https://www.ncbi.nlm.nih.gov/pubmed/22910362
15.  Zhang CC, Zhu JX, Wan Y, Tan L, Wang HF, Yu JT, Tan L: Meta-analysis of the association between variants in MAPT and neurodegenerative diseases. Oncotarget. 2017. https://www.ncbi.nlm.nih.gov/pubmed/28402959
16.  Georgieva ER, Xiao S, Borbat PP, Freed JH, Eliezer D: Tau binds to lipid membrane surfaces via short amphipathic helices located in its microtubule-binding repeats. Biophys J. 2014;107(6):1441-1452. PMC4167292. https://www.ncbi.nlm.nih.gov/pubmed/25229151
17.  Deng H, Gao K, Jankovic J: The VPS35 gene and Parkinson’s disease. Mov Disord. 2013;28(5):569-575. https://www.ncbi.nlm.nih.gov/pubmed/23536430
18.  Kubo S, Hatano T, Hattori N: Lipid rafts involvement in the pathogenesis of Parkinson’s disease. Front Biosci (Landmark Ed). 2015;20(263-279. https://www.ncbi.nlm.nih.gov/pubmed/25553450