Using LIS1 missense mutations to probe dynein regulatory mechanisms

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SUMMARY: It is becoming clear that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. For example, pathways that control the microtubule motor cytoplasmic dynein 1 (hereafter referred to as “dynein”) are perturbed in multiple disorders from cortical malformations to ALS and other degenerative diseases [1]. This motor is indispensable for a wide range of cellular processes in the developing and mature nervous system [2]. Our group is interested in the dynein regulatory protein, LIS1. As a vital dynein regulator, it is surprising that PAFAH1B1 mutations have not been found in other neurological diseases. We are currently studying a novel LIS1 missense mutation (K351R) in a boy with Autism Spectrum Disorder (ASD), supporting the possibility that some LIS1 mutations can lead to less severe disease. Most, if not all, LIS1 roles are related to dynein regulation. Around 20 genes encoding LIS1-interacting or dynein regulatory proteins that have potential autism spectrum disorder (ASD)-linked mutations, so perturbations in dynein regulation could predispose to ASD. There are other missense mutations that could lead to partially functional proteins in several online databases. In this R21 exploratory project we will test the hypothesis that individual LIS1 missense mutations will disrupt specific LIS1 interactions, thereby differentially regulating dynein and impacting disease severity. We will determine how each mutation impacts critical LIS1 interactions, and how they impact LIS1’s ability to regulate dynein. This study will be the first to systematically dissect the impact of LIS1 missense mutations in different domains of the protein on dynein function, and to correlate changes in dynein function with disease severity. As neurons are uniquely sensitive to reduced LIS1 expression they might be negatively impacted even by small changes in LIS1 that subtly alter dynein function. Because LIS1 is critical in both the developing and adult nervous system, our studies could provide a springboard for understanding dynein deregulation across a wide range of neurological disorders, including ASD and later onset disorders such as Alzheimer’s Disease and Amyotrophic Lateral Sclerosis.