GSBS Dissertations and Theses

ORCID ID

0000-0002-5940-1867

Publication Date

2020-09-21

Document Type

Doctoral Dissertation

Academic Program

Neuroscience

Department

Neurology

First Thesis Advisor

Daryl Bosco

Keywords

ALS, nuclear pore, RNA-binding protein, neurodegeneration, nucleocytoplasmic transport, FUS

Abstract

Nucleocytoplasmic transport (NCT) declines during aging and in the context of age-dependent neurodegenerative diseases. However, the mechanisms underlying NCT decline in the disease are poorly understood. FUS is an RNA binding protein that shuttles between the nucleus and cytoplasm and is actively involved in NCT. Mutations in FUS cause amyotrophic lateral sclerosis (ALS), a fatal and incurable motor neuron disorder. We sought to understand the disease mechanism underlying FUS-induced NCT decline in ALS.

Here, I uncovered NCT-related defects in motor neurons derived from human induced pluripotent stem cells (iPSCs) harboring an ALS-linked FUS mutation. Importantly, these NCT defects were rescued by genetically correcting the FUS mutation in iPSCs. To gain insight into how expression of mutant FUS causes nuclear pore defects, I demonstrated an altered localization where FUS and nucleoporins (Nups) interact in situ within patient-derived human neurons. Moreover, FUS became aggregation-prone when interacting with Nup62 in vitro, and RNA further alleviated their aggregation propensity. Importantly, NCT-related defects and neuronal toxicity induced by ALS-FUS were ameliorated by modulating Nup expression in vivo. Collectively, these findings implicate aberrant Nup interactions in the pathogenic mechanism of ALS-FUS, and direct targeting the gain-of-function protein interactions could be therapeutic for multiple causes of neurodegeneration.

DOI

10.13028/80pm-9c07

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Available for download on Thursday, October 06, 2022

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