Parkinson's disease (PD) is becoming recognized to be an illness driven by intricate genetic links as opposed to individual gene alterations. The scope of this issue is highlighted in the 2025 study "Genetic Modifiers of Parkinson’s Disease: A Case–Control Study" by Matthew J. Kmiecik and colleagues, which looks at how multiple genetic histories and other alleles, like APOE E4, work together with recognizable pathogenic variants, like LRRK2 p.G2019S and GBA1 p.N409S, to influence both the likelihood of developing the disease and symptoms (Kmiecik, 2025). The investigators discovered that the overall prevalence of PD by age 80 approached roughly “30% in dual carriers of LRRK2 and GBA1, in contrast to 24% in LRRK2-only carriers, 4% in GBA1-only carriers, and 2% in noncarriers” in an overall population of over 35,000 people with PD as well as more than 7.5 million control subjects (Kmiecik, 2025). Additionally, the research found that although non-motor signs seemed more common in GBA1 carriers and comparatively uncommon in LRRK2 carriers, greater levels of polygenic risk appeared to be linked to quicker onset and greater likelihood of disease (Kmiecik, 2025). The results emphasize that the interaction of significant variations along with the larger genetic setting modulates impact; genetic vulnerability itself cannot predict PD onset.
This perspective is further expanded by an associated investigation conducted by Northwestern University Feinberg School of Medicine, which uses a genome-wide CRISPR interference screen to find formerly unidentified genetic factors (“New key genes in Parkinson’s disease identified using CRISPR technology”, 2025). The "Commander complex," a collection of proteins that affect the likelihood of Parkinson's by controlling lysosomal activity, was emphasized in this study, which concentrated on suppressing almost all protein-coding genes within human cell systems (“New key genes in Parkinson’s disease identified using CRISPR technology”, 2025). PD has historically been linked to the lysosome, an essential structure for removing impaired proteins and cellular detritus, particularly via the GBA1 gene that codes for glucocerebrosidase (“New key genes in Parkinson’s disease identified using CRISPR technology”, 2025). The work shows that loss-of-function variations in Commander complex genes raise the likelihood of Parkinson's disease (PD), indicating that lysosomal malfunction may influence disease risk in addition to recognized significant mutations (“New key genes in Parkinson’s disease identified using CRISPR technology”, 2025).
A more complex understanding of PD genetics is provided by combining both of these investigations. While the CRISPR-based investigation reveals new pathways that regulate susceptibility at the cellular level, the condition-controlled analysis confirms how significant pathogenic mutations communicate with the diverse genetic makeup to impact illness onset and symptoms. Together, these results demonstrate that the likelihood of Parkinson's disease (PD) is influenced by a variety of both inherited and molecular elements, where severity, age of diagnosis, and symptoms are determined by the interaction of both notable abnormalities and larger networks of cells. This complicated interaction suggests lysosomal transport as a possible target for upcoming therapeutic approaches and provides an explanation for why certain carriers of high-risk mutations rarely acquire the illness whereas others show quick and serious symptoms.
These results identify the significance of going past single-gene approaches in order to comprehend Parkinson's disease (PD) as an interconnected disease. Significant variations, a mixed genetic history, and additional cellular regulators all contribute to the genetic structure of Parkinson's disease (PD). This implies that thorough genetic testing may give patients and medical professionals greater understanding of clinical treatment, disease diagnosis, and qualification for specific therapies. In order to identify the molecular pathways behind Parkinson's disease (PD), researchers must integrate functional DNA sequencing, systems biology, and broad-ranging genetic data. Utilizing both of these methods brings us closer to tailored and predictive techniques that tackle the complex genomic pathways that influence the development of diseases in addition to the major abnormalities.
References:
New key genes in Parkinson’s disease identified using CRISPR technology. (2025). Northwestern.edu; Northwestern Now. https://news.northwestern.edu/stories/2025/04/new-key-genes-in-parkinsons-disease-identified-using-crispr-technology
Kmiecik, M. J., Holmes, M. V., Fontanillas, P., Riboldi, G. M., Schneider, R. B., Shi, J., Guan, A., Tat, S., Micheletti, S., Stagaman, K., Gottesman, J., Hinds, D. A., Tung, J. Y., Aslibekyan, S., & Norcliffe‐Kaufmann, L. (2025). Genetic Modifiers of Parkinson’s Disease: A Case–Control Study. Annals of Clinical and Translational Neurology. https://doi.org/10.1002/acn3.70176
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