The Genetic Landscape of Parkinsonism-Related Dystonias and Atypical Parkinsonism-Related Syndromes.

In recent decades, genetic research has nominated promising pathways and biological insights contributing to the etiological landscape of parkinsonism-related dystonias and atypical parkinsonism-related syndromes. Several disease-causing mutations and genetic risk factors have been unraveled, providing a deeper molecular understanding of the complex genetic architecture underlying these conditions. These disorders are difficult to accurately diagnose and categorize, thus making genetics research challenging. On one hand, dystonia is an umbrella term linked to clinically heterogeneous forms of disease including dopa-responsive dystonia, myoclonus-dystonia, rapid-onset dystonia-parkinsonism and dystonia-parkinsonism, often viewed as a precursor to Parkinson's disease. On the other hand, atypical parkinsonism disorders, such as progressive supranuclear palsy, multiple system atrophy and corticobasal degeneration, are rare in nature and represent a wide range of diverse and overlapping phenotypic variabilities, with genetic research limited by sample size availability. The current review summarizes the plethora of available genetic information for these diseases, outlining limits and future directions.

Comparison of tumor growth assessment using GFP fluorescence and DiI labeling in a zebrafish xenograft model.

DiI is a lipophilic fluorescent dye frequently used to label and trace cells in cell cultures and xenograft models. However, DiI can also transfer from labeled to unlabeled cells, including host organism cells, and label dead cells obscuring interpretation of the results. These limitations of DiI labeling in xenograft models have not been thoroughly investigated. Here we labeled green fluorescent protein (GFP)-expressing MDA-MB-231 cells with DiI to directly compare tumor growth assessment in zebrafish xenografts using the DiI labeling and GFP fluorescence. Our results indicate that the DiI based assessment significantly overestimated tumor growth in zebrafish xenograft models compared to the GFP fluorescence based assessment. The imaging of DiI labeled GFP-expressing MDA-MB-231 cell cultures indicated that the DiI labeling of the membrane is uneven. Analysis of the DiI labeled GFP-expressing MDA-MB-231 cell cultures with flow cytometry indicated that the DiI labeling varied over time while the GFP fluorescence remained unchanged, suggesting that the GFP fluorescence is a more reliable signal for monitoring tumor progression than the DiI labeling. Taken together, our results demonstrate limitations of using DiI labeling for xenograft models and emphasize the need for validating the results based on DiI labeling with other orthogonal methods, such as the ones utilizing genetically encoded fluorophores.

Polygenic risk score for Parkinson's disease and olfaction among middle-aged to older women.

INTRODUCTION: Olfactory impairment and Parkinson's disease (PD) may share common genetic and environmental risk factors. This study investigates the association of a PD polygenic risk score (PRS) with olfaction, and whether the associations are modified by environmental exposures of PM2.5, NO2, or smoking. METHODS: This analysis included 3358 women (aged 50-80) from the Sister Study with genetic data and results from the Brief Smell Identification Test (B-SIT) administered in 2018-2019. PD PRS was calculated using 90 single nucleotide polymorphisms. Olfactory impairment was defined with different B-SIT cutoffs, and PD diagnosis was adjudicated via expert review. We report odds ratios (ORs) and 95% confidence intervals (CIs) from multivariable logistic regression. RESULTS: As expected, PD PRS was strongly associated with the odds of having PD (OR highest vs. lowest quartile = 3.79 (1.64, 8.73)). The highest PRS quartile was also associated with olfactory impairment, with OR ranging from 1.24 (0.98, 1.56) for a B-SIT cutoff of 9 to 1.42 (1.04, 1.92) for a cutoff of 6. For individual B-SIT items, the highest PRS quartile was generally associated with lower odds of correctly identifying the odorant, albeit only statistically significant for pineapple (0.72 (0.56, 0.94), soap (0.76 (0.58, 0.99)) and rose (0.70 (0.54, 0.92)). The association of PD PRS with olfactory impairment was not modified by airborne environmental exposures or smoking. CONCLUSION: These preliminary data suggest that high PD genetic susceptibility is associated with olfactory impairment in middle-aged and older women.

The Foundational Data Initiative for Parkinson Disease: Enabling efficient translation from genetic maps to mechanism.

The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.