Over the past two decades, researchers have documented numerous links between Parkinson’s disease and Gaucher disease. Rare patients with Gaucher disease show parkinsonian symptoms¹ and many more have family members with Parkinson’s disease.² Lewy bodies—large aggregates of alpha synuclein protein characteristic of Parkinson’s disease—have been identified in the brains of Gaucher patients,³ and approximately 5-10% of those with sporadic Parkinson’s disease show mutations in the glucocerebrosidase gene, the cause of Gaucher disease.^4,5

Glucocerebrosidase is a lysosomal enzyme that catalyzes the breakdown of glucocerebroside into glucose and ceramide. Most Gaucher disease causing mutations lead to a reduction in the stability or activity of glucocerebrosidase and its accumulation in lysosomes. Misfolded glucocerebrosidase also places stress on the endoplasmic reticulum that may contribute to pathology.⁶

The strong association between mutations in the glucocerebrosidase gene GBA1 and Parkinson’s disease implicates lysosomal dysfunction in Parkinson’s disease pathology. Lysosomes are part of the autophagy and mitophagy pathways that degrade unwanted cellular proteins, organelles, and mitochondria. Consequently, lysosomal dysfunction has the potential to broadly disrupt cellular degradation processes.

However, the mechanism by which GBA1 mutations increase the risk for Parkinson’s disease is not yet established. Some evidence supports a loss of function hypothesis in which reduced glucocerebrosidase function leads to reduced degradation of alpha synuclein, whereas other evidence favors a gain of function explanation in which the mutated glucocerebrosidase stimulates the formation of alpha synuclein oligomers.⁶ Given that most individuals with GBA1 mutations do not develop Parkinson’s disease, other genetic, epigenetic, or environmental factors must play a role.

Many of the documented mutations that cause or increase the risk of Parkinson’s disease have been linked to cellular degradation processes—alpha synuclein overproduction and accumulation (SNCA gene), lysosomal function (GBA1 gene), lysosomal genesis and protein recycling (VPS35 gene), mitophagy (PINK1, PARK2, and LRRK2 genes), and autophagy (LRRK2 and DJ-1 genes). Strategies to enhance these processes are being investigated in preclinical models.⁷

A difficult question for the future will be to identify factors that combine with the known genetic variations to cause overt disease. Analyses based on genome wide association studies suggest that pathways related to cell structure and adhesion may be fruitful avenues of inquiry.^8,9 For instance, mitochondria bind to microtubule motors through the protein Miro, and removal of Miro is a signal for mitochondrial degradation. Mutations in LRRK2, PINK1, and PARK2 all interfere with this process.^10,11 Similarly, the cytoskeleton is critically involved in autophagy.¹²  Vesicles and organelles that participate in mitophagy, autophagy, and neurotransmission are guided around cells by structural proteins, yet few studies have investigated potential links to Parkinson’s disease.

References

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4.  Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E: Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 2004’81(1):70-73.
5.  Ran C, Brodin L, Forsgren L, Westerlund M, Ramezani M, Gellhaar S, et al: Strong association between glucocerebrosidase mutations and parkinson’s disease in sweden. Neurobiol Aging 2016;45(212 e215-212 e211.
6.  Migdalska-Richards A, Schapira AH: The relationship between glucocerebrosidase mutations and parkinson disease. J Neurochem 2016;139 (suppl 1)(77-90.
7.  Aflaki E, Borger DK, Moaven N, Stubblefield BK, Rogers SA, Patnaik S, et al: A new glucocerebrosidase chaperone reduces alpha-synuclein and glycolipid levels in ipsc-derived dopaminergic neurons from patients with gaucher disease and parkinsonism. J Neurosci 2016;36(28):7441-7452.
8.  Hu Y, Deng L, Zhang J, Fang X, Mei P, Cao X, Lin J, Wei Y, Zhang X, Xu R: A pooling genome-wide association study combining a pathway analysis for typical sporadic parkinson’s disease in the Han population of Chinese mainland. Mol Neurobiol 2016;53(7):4302-4318.
9.  Edwards YJ, Beecham GW, Scott WK, Khuri S, Bademci G, Tekin D, et al: Identifying consensus disease pathways in parkinson’s disease using an integrative systems biology approach. PLoS One 2011;6(2):e16917.
10.  Hsieh CH, Shaltouki A, Gonzalez AE, Bettencourt da Cruz A, Burbulla LF, St Lawrence E, et al: Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic parkinson’s disease. Cell Stem Cell 2016.
11.  Weihofen A, Thomas KJ, Ostaszewski BL, Cookson MR, Selkoe DJ: Pink1 forms a multiprotein complex with miro and milton, linking pink1 function to mitochondrial trafficking. Biochemistry 2009;48(9):2045-2052.
12.  Monastyrska I, Rieter E, Klionsky DJ, Reggiori F: Multiple roles of the cytoskeleton in autophagy. Biol Rev Camb Philos Soc 2009;84(3):431-448.