Towards the end of the semester, we had Dr. Matthew Kmiecik present on the topic of genetic modifiers that influenced risk factors and symptoms associated with Parkinson’s disease. It is a brain disorder that affects the nervous system by causing a loss of dopaminergic neurons that play a role in neurotransmission, leading to uncontrollable tremors throughout the body. Not only this, but it can also have hidden symptoms like depression, anxiety, dementia, etc. Dr. Kmiecik connected the expression of two specific genetic variants linked to PD risk in the article titled “Genetic Modifiers of Parkinson’s disease: A Case-Control Study,” while also providing background information on his research. To understand Parkinson’s disease, the hypothesized mechanism for how Parkinson’s comes to unfold was used. A protein known as alpha-syn, which is involved in synaptic transmission, misfolds, causing clumps of the misfolded protein to accumulate. This accumulation is known as Lewy bodies, which are toxic to neurons. Although both genetic and environmental factors influence risk, data from 23andMe and Fox Insight researched the chromosomal genetic variations known as LRRK2 and GBA1, as well as the APOE E4 allele. LRRK2 is a kinase protein involved in neuron communication, cell recycling, cell energy, immune response, and cell structure. Even though this protein is detrimental to so many processes, the accumulation of this protein can increase Lewy bodies and leading to neuronal loss. GBA1 is a bit different in that it encodes GCase and degrades GlcCer, a sugar for cellular processes. GlcCer also begins to build up, leading to Lewy bodies. APOE E4 was then seen to increase the risk of PD. Researchers then compared carriers vs noncarriers of all these genes and found that carriers of both LRRK2 and GBA1 were actually protected from the effects of GBA1, but were still at high risk of developing PD. Those with only GBA1 had a smaller risk of developing PD in comparison to the single LRRK2 variant. With all these different genes at play, it was noted that the symptoms ultimately differentiated from person to person, further proving that the two mutations have distinct disease pathways. When pairing APOE E4 as an allele to either gene, people noted a bigger risk for certain symptoms such as hallucinations and impairments, but not as an interactive risk. This information regarding genetic variation can further explain how environmental factors, such as pesticides, impact a higher expression of symptoms within Parkinson’s.
In the article, “Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in rotenone Parkinson’s model,” Tsalenchuk et al. investigated the molecular effects of the pesticide rotenone, which is an environmental risk factor for Parkinson’s disease, on rat models. Researchers investigated histone acetylation (H3K27ac) and gene expression in the substantia nigra (SN) and motor cortex, along with the changes seen in those regions specific to Parkinson’s. Rotenone inhibits mitochondrial complex I throughout the brain, causing oxidative stress and leading to neuronal impairments. To go along with this, rotenone also induces alpha-syn, which is known to harm the substantia nigra and gastrointestinal tract, causing non-motor symptoms seen in those with PD. With the neurodegeneration occurring in the SN due to rotenone, an enhanced immune response occurs, causing inflammatory responses that are driven by altered gene regulation. In the motor cortex, the gene regulatory changes affected synaptic mechanisms, with hyper- and hypoacetylated regions that are critical for excitatory synapse function. This is linked to PD progression as it can lead to an overload of excitatory signaling and stabilization of synaptic complexes due to changes within genes such as HOMER1, GRIN2B, and SHANK1.
Both studies dive into Parkinson’s disease and the genetic and environmental factors that influence the symptoms to emerge. While neither directly gives a cause for why Parkinson’s occurs, they dive into what could be causing the development of this disease. Pesticides like rotenone and genetic variants such as LRRK2 and GBA1contribute to the increase of symptoms, both motor and non-motor. Dr. Kmiecik explained that by the age of 80, carriers for either gene mentioned above increased their penetrance, which is the percent that is predicted to develop PD. Pesticides go along with this as they impact neurons within the substantia nigra and motor cortex, leading to impairments. From all the research mentioned above, one can conclude that many factors play a role in the evolution of Parkinson’s. Researching the genetics of PD allows for a better understanding of cellular mechanisms, which allows for the involvement of environmental factors, such as pesticides, to be looked at more closely to further help in treating patients with Parkinson’s.
References
Kmiecik, Matthew J et al. “Genetic Modifiers of Parkinson's Disease: A Case-Control Study.” Annals of clinical and translational neurology, 10.1002/acn3.70176. 10 Sep. 2025, doi:10.1002/acn3.70176
Tsalenchuk, M., Farmer, K., Castro, S. et al. Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in rotenone Parkinson’s model. npj Parkinsons Dis. 11, 217 (2025). https://doi.org/10.1038/s41531-025-01049-1
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