A multi-region single nucleus transcriptomic atlas of Parkinson's disease

Abstract

Parkinson's Disease (PD) is a debilitating neurodegenerative disorder, characterized by motor and cognitive impairments, that affects >1% of the population over the age of 60. The pathogenesis of PD is complex and remains largely unknown. Due to the cellular heterogeneity of the human brain and changes in cell type composition with disease progression, this complexity cannot be fully captured with bulk tissue studies. To address this, we generated single-nucleus RNA sequencing and whole-genome sequencing data from 100 postmortem cases and controls, carefully selected to represent the entire spectrum of PD neuropathological severity and diverse clinical symptoms. The single nucleus data were generated from five brain regions, capturing the subcortical and cortical spread of PD pathology. Rigorous preprocessing and quality control were applied to ensure data reliability. Committed to collaborative research and open science, this dataset is available on the AMP PD Knowledge Platform, offering researchers a valuable tool to explore the molecular bases of PD and accelerate advances in understanding and treating the disease.

Fig. 1

Schematic overview of dataset collection and main study deliverables. Harvard: NIH NeuroBiobank at the Harvard Brain Tissue Resource Center; MSSM: NIH NeuroBioBank at the Mount Sinai Brain Bank; Udall: University of Miami Udall Center of Excellence for Parkinson's Disease Research; UMiami: NIH NeuroBioBank at the University of Miami and University of Miami Brain Endowment Bank.

Fig. 2

Study cohort characteristics. (a–c) Numbers and distributions of male and female donors across brain regions and age. (d) Distribution of donors by the most similar ancestry superpopulation predicted by QDA (AFR: African, AMR: Admixed American, EUR: European, SAS: South Asian). (e–g) Distribution of donors by age, source brain bank and Braak PD staging. (h) Spearman correlation coefficients among PD-related phenotypes. Harvard: NIH NeuroBiobank at the Harvard Brain Tissue Resource Center; MSSM: NIH NeuroBioBank at the Mount Sinai Brain Bank; Udall: University of Miami Udall Center of Excellence for Parkinson's Disease Research; UMiami: NIH NeuroBioBank at the University of Miami and University of Miami Brain Endowment Bank.

Fig. 3

Analysis of snRNA-seq dataset. (a) Distribution of the number of nuclei across sequencing pools. Horizontal dashed line denotes a mean value. (b) Distribution of nuclei to replicates within pools, ordered by cell count. Each replicate is depicted using two boxplots representing the nuclei distribution before and after QC. The center line (black) indicates the median, the box shows the interquartile range, and the whiskers indicate the highest/lowest values within 1.5× the interquartile range. (c) Comparison of QC-passed nuclei counts between pairs of replicates from the same pools shows high consistency (Spearman’s ρ=0.79). (d) Distribution of nuclei counts in samples that passed or failed QC (vertical line indicates the mean values). (e) Sample counts and intersections among brain regions. (f) nuclei distribution across five brain regions. The left y-axis shows the average number of nuclei per sample for each region, while the right y-axis indicates the total number of nuclei detected in all samples from each region. (g) UMAP visualization of single nuclei defined by RNA-seq data shows eight major cell type clusters that are expected to be presented in the investigated brain regions.

Fig. 4

Quality control of WGS data. (a) Distribution of mean coverage indicating the average number of high-quality sequencing reads per base after applying all QC steps. (b) The fraction of the genome sequenced at different depths. The center line (black) indicates the median, the box shows the interquartile range, and the whiskers indicate the highest/lowest values within 1.5× the interquartile range. (c,d) Number of per-sample SNPs and indels. (e) Sex check based on comparison of the counts of heterozygous and homozygous alleles. (f) The first two PCs of genetic ancestry. (g) Pairwise comparison of the SNPs among all putatively matched and non-matched combinations of WGS samples. (h) Pairwise comparison of the genetic similarities calculated by QTLtools-mbv between WGS samples and genotypes called from snRNA-seq data.