“Genetics loads the gun and environment pulls the trigger” is often invoked when discussing the etiology of a multitude of conditions, including Parkinson’s disease. The interplay between genetics and environmental risk factors is the basis of much of the current research in Parkinson’s. More than 12% of 13,000 participants have tested positive for one of seven genetic variants associated with Parkinson’s in an ongoing landmark clinical study, PD GENEration, sponsored by the Parkinson’s Foundation. As a companion article to our most recent Insights post on environmental risk factors, this final article in our series on mechanisms and risk factors for Parkinson’s will highlight a few of the most frequently identified genetic mutations and associated inflammatory mechanisms that play a key role in the pathogenesis of Parkinson’s disease.

SNCA:
SNCA (synuclein alpha) was the first Parkinson’s-related gene to be identified in 1997, and this led to the discovery of the protein it encodes: alpha-synuclein, the main component of the pathologic hallmark of Parkinson’s, the Lewy body. SNCA mutations result in either misfolding or aggregation of alpha-synuclein, thereby activating pro-inflammatory microglia, an immune system cell necessary for clearing cellular debris, including alpha-synuclein protein aggregates. This promotes the production of cytokines, which are chemical messages secreted by cells of the immune system, such as IL-1β. Aggregation also leads to oxidative stress (an imbalance between harmful free radicals and antioxidants) and further contributes to inflammation and eventual neurotoxicity.

LRRK2:
Mutations of the LRRK2 (leucine rich repeat kinase 2) gene play a role in about 1% of all cases of Parkinson’s and 5% of familial Parkinson’s. Parkinson’s-associated LRRK2 mutations are associated with reduced lysosome (debris-clearing organelle) activity in microglia, which leads to further cellular dysfunction and nigral cell death. Lysosomal activity in macrophages, another type of immune cell, may also be affected by the Parkinson’s-associated LRRK2-G2019S mutation. This mutation also contributes to genetic risk for Crohn’s disease, an autoimmune disorder of the gastrointestinal system. This is an example of a common pathway for genetic influences of the immune system as causative for disease.

PRKN/PINK1:
In patients carrying mutations in PRKN (parkin RBR E3 ubiquitin protein ligase) or PINK1 genes, increased levels of mitochondrial DNA and interleukin-6 (IL-6) have been identified. These mutations result in impaired degradation of mitochondria (mitophagy), which causes the release of mitochondrial DNA, thereby triggering inflammation and the elevation of IL-6, an inflammatory marker associated with neurodegeneration. In one study, patients with two copies of the mutation showed elevated levels of IL-6 compared to patients with only one copy of the mutation (heterozygous patients). The study also showed that elevated IL-6 levels could be detected in serum even before clinical manifestations of Parkinson’s disease.

GBA:
GBA (glucosylceramidase beta) is the most common Parkinson’s-related gene, present in 5 to 10% of people with Parkinson’s. The GBA gene produces a protein called GCase (glucocerebrosidase), which is a lysosomal enzyme, and variants in GBA have been linked to further build-up of alpha-synuclein in Parkinson’s. One recent study showed that the peripheral immune system is also affected differently in Parkinson’s patients with GBA mutations, with lower lymphocyte counts and higher neutrophil counts. Although the implications of these findings are unclear, authors suggest this might lead to an inability to suppress inflammation contributing to the loss of dopaminergic neurons.

A Look Ahead:
Until very recently, most studies of genetics in Parkinson’s have included individuals of European ancestry. In January 2024, an article published in Nature Genetics became the largest genetically diverse study of Parkinson’s disease to date, including 49,049 patients of European, East Asian, Latin American, and African ancestry. This was a genome-wide association study (GWAS) allowing for identification of genetic variants across populations. In some populations, a variant may confer an increased risk of Parkinson’s, but in other populations, the same variant may be protective. Ongoing collaborative efforts such as the Global Parkinson’s Genetics Program (GP2) will help us learn more about Parkinson’s in different populations, thereby opening doors for the possibility of more targeted, and therefore more effective, treatments for more people.

Understanding the genetics of Parkinson’s disease is helping researchers gain insights in terms of disease mechanisms, in turn leading to an array of candidates for treatment. It is entirely possible that future approaches to managing Parkinson’s disease will expand beyond treating symptoms as they develop. Efforts are expected to surpass the focus on dopamine, in favor of a multi-pronged approach, with gene therapy, drug candidates that address alpha-synuclein and an overactive immune system, and even lifestyle choices such as exercise that could prevent neuronal cell loss. Identification of risk factors earlier in the course of Parkinson’s, along with earlier and more accurate diagnostic strategies, will pave the way for disease modification and even prevention.

References:

Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V. Inflammation and immune dysfunction in Parkinson disease. Nat Rev Immunol. 2022;22(11):657-673. doi:10.1038/s41577-022-00684-6

Yi M, Li J, Jian S, et al. Quantitative and causal analysis for inflammatory genes and the risk of Parkinson’s disease. Front Immunol. 2023;14:1119315. doi:10.3389/fimmu.2023.1119315

Borsche M, König IR, Delcambre S, et al. Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism. Brain. 2020;143(10):3041-3051. doi:10.1093/brain/awaa246

Muñoz-Delgado L, Macías-García D, Periñán MT, et al. Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease [published correction appears in NPJ Parkinsons Dis. 2023 Feb 17;9(1):27]. NPJ Parkinsons Dis. 2023;9(1):12. doi:10.1038/s41531-023-00457-5

Kim JJ, Vitale D, Otani DV, et al. Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease. Nat Genet. 2024;56(1):27-36. doi:10.1038/s41588-023-01584-8

de Laat B, Hoye J, Stanley G, et al. Intense exercise increases dopamine transporter and neuromelanin concentrations in the substantia nigra in Parkinson’s disease. NPJ Parkinsons Dis. 2024;10(1):34. doi:10.1038/s41531-024-00641-1