In the second half of the semester, our class had the pleasure of listening to Matt Kmiecik present his research on the effects of LRRK2, GBA1, APOE E4, and polygenic risk scores on symptoms and risk of Parkinson’s disease. His studies aimed to determine the effects of these genetic modifiers on PD penetrance, risk, and symptoms by examining participants with and without PD who either carry two, none, or one of the genes. To do so, an observational case-control study was performed using data from 23andMe and FIGS databases. Their results showed that by the age of 80, carriers of both LRRK2 and GBA1 had PD 30% of the time, those with only LRRK2 had PD 24% of the time, those with GBA1 only had PD 4% of the time, and non-carriers 2% of the time. These results suggest that the most strongly associated genetic modifier of PD is the LRRK2 gene. However, LRRK2 was associated with the lowest amount of non-motor symptoms of PD. In Kmiecik’s journal article, LRRK2 is described as a gene that encodes for a kinase and GTPase complex that often results in a gain of function in the kinase domain that leads to PD. This happens because it can cause a neurodegenerative process in the substantia nigra. The phenotypic data show that the risk of PD was highest in those carrying the LRRK2 gene and dual carriers.
After hearing Matt Kmiecik’s presentation and reading his journal article, I wondered if the findings of his research and the knowledge that exists of the genetic modifiers of PD could possibly be used in the future to develop technology that helps to prevent or treat it. Another journal article by Sun-Ku Chung and Seo-Young Lee, Advances in Gene Therapy Techniques to Treat LRRK2 Gene Mutation, examines the LRRK2 gene, its involvement in PD, and how the technology of gene correction (CRISPR/Cas-9-HDR, ZFN, and ABE) can be applied to the LRRK2 gene to potentially decrease the risk of PD. Chung and Lee explain that the LRRK2 gene mutation is particularly prevalent in familial PD and that recent methods of gene replacement therapy, like zinc finger nuclease (ZFN) and adenine base editor (ABE), have been used for LRRK2 genes with high mutation frequencies. ZFN-mediated LRRK2 gene targeting uses 3-6 zinc finger motifs that bind to DNA to allow the restriction enzyme FokI to cleave it. The ZFNs bind on the left and right sides of the desired target sequence before cleaving. Since LRRK2 can induce the degeneration of dopaminergic neurons in the midbrain, cause neurite shortening, and increase apoptotic sensitivity to neurotoxins, its removal alleviates its damaging effects and lessens PD progression. CRISPR/Cas9 gene targeting has also been used to remove the LRRK2 gene. Although not used to correct the mutation, previous studies have investigated the LRRK2 gene using CRISPR technology, concluding that the gene mutation significantly affects the neurite length and branches in dopaminergic neurons. Although CRISPR/Cas9 can be used to correct gene mutations, it also tends to cause off-target effects and leave unintended scars around the target DNA. To fix this, ABE-mediated gene targeting can be used to convert an adenine base into inosine, so that Cas9 only nicks one strand rather than creating a DSB. This reduces the damage that Cas9 can cause to neighboring regions of the target sequence. This article applies the findings from Kmiecik’s research and discusses how they can be used to examine methods of treatment, given what we know about genetic modifiers and gene editing. It concludes that genetic correction therapies are promising as a future method of PD treatment, and that clinical trials investigating their usage are in progress. I believe that research like Kmiecik’s and Chung and Lee’s is crucial to the development of treatments and preventative measures for any disease with genetic modifiers.
References
Chung, S.-K., & Lee, S.-Y. (2022). Advances in gene therapy techniques to treat LRRK2 gene mutation. Biomolecules, 12(12), 1814. https://doi.org/10.3390/biom12121814
Kmiecik, M. (2025). Genetic modifiers of Parkinson’s disease: A case-control study. Annals of Clinical and Translational Neurology. Advance online publication. https://doi.org/10.1002/acn3.70176
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