Protein network analysis links the NSL complex to Parkinson’s disease via mitochondrial and nuclear biology

Article published in Molecular Omics on 14 June 2023 (advanced). Initial Pre-print doi: 10.1101/2023.01.27.524249 posted on 27 January 2023 https://www.biorxiv.org/content/10.1101/2023.01.27.524249v1.full.pdf. Whilst the majority of Parkinson’s Disease (PD) cases are sporadic, much of our understanding of the pathophysiological basis of the disease can be traced back to the study of rare, monogenic forms of PD. In the past decade, the availability of genome-wide association studies (GWAS) has facilitated a shift in focus, toward identifying common risk variants conferring increased risk of developing PD across the population. A recent mitophagy screening assay of GWAS candidates has functionally implicated the non-specific lethal (NSL) complex in the regulation of PINK1-mitophagy. Here, a bioinformatics approach has been taken to investigate the proteome of the NSL complex, to unpick its relevance to PD pathogenesis. The NSL interactome has been built, using 3 online tools: PINOT, HIPPIE and MIST, to mine curated, literature-derived protein–protein interaction (PPI) data. We built (i) the ‘mitochondrial’ NSL interactome exploring its relevance to PD genetics and (ii) the PD-oriented NSL interactome to uncover biological pathways underpinning the NSL/PD association. In this study, we find the mitochondrial NSL interactome to be significantly enriched for the protein products of PD-associated genes, including the Mendelian PD genes LRRK2 and VPS35. In addition, we find nuclear processes to be amongst those most significantly enriched within the PD-associated NSL interactome. These findings strengthen the role of the NSL complex in sporadic and familial PD, mediated by both its mitochondrial and nuclear functions