Abstract

Stewart W. Humble1,2,3, Brent Ryan2, Michael E. Ward1 and Richard Wade-Martins2 1. Inherited Neurodegenerative Diseases Unit, Neurogenetics Branch, NINDS, National Institutes of Health, MD. 2. Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, and Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK. 3. Louisiana State University Health Sciences Center, New Orleans School of Medicine, New Orleans, LA. Parkinson’s disease (PD) and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTD/ALS) are progressive neurodegenerative diseases that are neuropathologically defined by the presence of protein aggregates and the loss of specific subsets of neurons. Both diseases are associated with variants in genes that are implicated in lysosome function and proteostasis. Therefore, it is likely that converging disease pathways exist across these subsets of neurodegeneration, and the interrogation of these pathways can be used both to enhance our understanding of these disorders and lead to innovative therapeutic interventions. We are currently utilizing our modified i3Neuron platform to facilitate systematic single and pairwise knockdown (KD) of large panels of PD and FTD/ALS-associated genes through CRISPR interference (CRISPRi) to interrogate gene-gene interactions. Our efforts have focused on generating the first genetic interaction maps between the major genetic causes and risk factors of PD and FTD/ALS. Most notably, our interaction screen has identified several validated gene-gene interaction candidates. TMEM106B, a modulator of both TDP-43 and GRN biology, was a component of multiple hits. Further analysis demonstrated that lysosomal pH is significantly lower than in the non-targeting comparisons, indicating a positive overall effect on lysosomal function with TMEM106B knockdown. These promising initial results demonstrate that identifying common pathogenic changes elicited by disease genes can help us understand the underlying converging mechanisms in PD and FTD/ALS. Through these efforts, we hope to lay the groundwork for improved molecular understanding and therapeutic discovery.