Deep phenotyping of peripheral tissue facilitates mechanistic disease stratification in sporadic Parkinson’s disease

Publication date: Available online 11 February 2020Source: Progress in NeurobiologyAuthor(s): Phillippa J Carling, Heather Mortiboys, Claire Green, Simeon Mihaylov, Cynthia Sandor, Aurelie Schwartzentruber, Rosie Taylor, Wenbin Wei, Chris Hastings, Siew Wong, Christine Lo, Samuel Evetts, Hannah Clemmens, Matthew Wyles, Sam Willcox, Thomas Payne, Rachel Hughes, Laura Ferraiuolo, Caleb Webber, Winston HideAbstractMechanistic disease stratification will be crucial to develop a precision medicine approach for future disease modifying therapy in sporadic Parkinson’s disease (sPD). Mitochondrial and lysosomal dysfunction are key mechanisms in the pathogenesis of sPD and therefore promising targets for therapeutic intervention. We investigated mitochondrial and lysosomal function in skin fibroblasts of 100 sPD patients and 50 age-matched controls. A combination of cellular assays, RNA-seq based pathway analysis and genotyping was applied. Distinct subgroups with mitochondrial (mito-sPD) or lysosomal (lyso-sPD) dysfunction were identified. Mitochondrial dysfunction correlated with reduction in complex I and IV protein levels. RNA-seq based pathway analysis revealed marked activation of the lysosomal pathway with enrichment for lysosomal disease gene variants in lyso-sPD. Conversion of fibroblasts to induced neuronal progenitor cells and subsequent differentiation into tyrosine hydroxylase positive neurons confirmed and further enhanced both mitochondrial and lysosomal abnormalities...

Source: Progress in Neurobiology - February 13, 2020 Category: Neuroscience Source Type: research