Non-cell autonomous mechanism of Parkinson’s disease pathology caused by G2019S LRRK2 mutation in Ashkenazi Jewish patient: Single cell analysis

Abstract

Parkinson s disease (PD) is the second most prevalent neurodegenerative disease, characterized by the loss of the midbrain dopaminergic neurons, which leads to impaired motor and cognitive functions. PD is predominantly an idiopathic disease, however about 5% of cases are linked to hereditary mutations. The most common mutation in both familial and sporadic PD is the G2019S mutation of leucine-rich repeat kinase 2 (LRRK2) with high prevalence in Ashkenazi Jewish patients and in North African Arab patients. It is still not fully understood how this mutation leads to PD pathology. In this study, we derived induced pluripotent stem cells (iPSCs) from an Ashkenazi Jewish patient with G2019S LRRK2 mutation to isolate self-renewable multipotent neural stem cells (NSCs) and to model this form of PD in vitro. To investigate the cellular diversity and disease pathology in the NSCs, we used single cell RNA-seq transcriptomic profiling. The evidence suggests the existence of three subpopulations within the NSCs: a committed neuronal population, intermediate stage population and undifferentiated stage population. Unbiased single-cell transcriptomic analysis revealed differential expression and dysregulation of genes involved in PD pathology. The significantly affected genes were involved in mitochondrial function, DNA repair, protein degradation, oxidative stress, lysosome biogenesis, ubiquitination, endosome function, autophagy and mitochondrial quality control. The results suggest that G2019S LRRK2 mutation may affect multiple cell types in a non-cell autonomous mechanism of PD pathology and that unbiased single-cell transcriptomics holds promise for personalized medicine.