REDONE-PD: Reflections of Dopamine-Related Gene Mutations on Neurocognitive Functions in Healthy Controls and Parkinson’s Disease

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms, including significant changes in neurocognitive functions (NFs). Dopamine synthesis, a critical process in PD, is heavily impacted by genetic factors, contributing to motor dysfunction and neurocognitive impairment. While some genetic mutations have been linked to PD-related neurocognitive impairments, the specific impact of these mutations on NFs remains unclear. This study explores the relationship between mutations in dopamine synthesis-related genes and NFs in PD patients and healthy controls (HC). Using a gene sequencing dataset (INDELs and SNPs) from the PPMI repository that includes 171 dopamine synthesis-related genes, we applied t-tests to identify 34 significantly mutated genes. We considered subjective (self-reported) responses from the MDS-UPDRS for seven NFs (i.e., motor, autonomic function, behavior/psychological, executive function, sensory, sleep, and speech). To investigate the link between significantly mutated genes and neurocognitive performance, participants were grouped into healthy and PD groups, and then each group was split into mutated and non-mutated samples. For healthy controls, presence of mutation in CAMK2D, and NOSTRIN and absence of mutation in DDX17 found related to NF worsening. In case of PD samples, the presence of mutations in genes like B3GALT5, CHRNA2, SNX27, TRIP4, and UBQLN4 and absence of mutation in genes like ABCA7, INTS4, MYLK3, PRKG1, and PRKN were linked to worsening neurocognitive outcomes. Overall, these findings provide a deeper understanding of the genetic influences on neurocognitive functions in PD and highlight potential targets for future research and therapeutic strategies.