Date of Award

Spring 5-15-2018

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Multisystem proteinopathy (MSP) defines a spectrum of degenerative diseases unified by TDP-43 pathology that affect muscle, brain and bone. Mutations in several proteins (VCP, p62/SQSTM1, HNRNPA2B1, HNRNPA1) can all cause MSP via impairments in autophagic protein degradation (VCP and SQSTM1) or RNA granule dynamics (HNRNPA2B1 and HNRNPA1). Phenotypically, MSP mutations lead to variable penetrance of several phenotypes: Paget’s disease of the bone (PDB), rimmed vacuolar inclusion body myopathy (RV-IBM), amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). However, how a same mutation of a protein can develop different diseases remains unclear. Understanding of p62/SQSTM1 (SQSTM1) function is critical to answer this question. In this dissertation, we provide evidence that SQSTM1 is regulated via its UBA domain ubiquitination. We find that Keap1/Cullin3 ubiquitinates SQSTM1 at lysine 420 within its UBA domain. Substitution of lysine 420 with arginine or disease-associated mutation of SQSTM1 disrupts its ubiquitination, sequestering activity, and degradation. In contrast, overexpression of Keap1/Cullin3 in SQSTM1-WT expressing cells increases ubiquitinated inclusion formation, SQSTM1’s association with autophagosomes and rescues proteotoxicity.

We also provide evidence that the oligogenic inheritance of a disease associated SQSTM1 mutation with a rare coding variant in the low-complexity domain (LCD) of the RNA-binding protein, TIA1 (p.N357S) can dictate a myodegenerative phenotypes. Deletion or mutation of SQSTM1 along with TIA1 disease mutants synergistically impairs RNA stress granules clearance and their dynamics. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin mediated autophagic degradation that defines the penetrance of a MSP phenotype.

Language

English (en)

Chair and Committee

Conrad Weihl

Committee Members

Abhinav Diwan, Phyllis Hanson, Timothy Miller, Heather True,

Comments

Permanent URL: https://doi.org/10.7936/K7PZ588W

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