Title

Uncovering novel roles for glia in neurodegenerative diseases

Date of Award

Spring 2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Interdepartmental Neuroscience Program

First Advisor

Lim, Janghoo

Abstract

The complexity of the central nervous system poses a tremendous challenge for understanding the intricate interplay between the myriad cell types that comprise the brain and spinal cord. Understanding these interactions becomes especially challenging when examining dynamic processes, such as aging or disease. In genetic disorders, an additional layer of complexity emerges when multiple cell types express the disease-causing or disease-associated proteins, as this expression can contribute to pathophysiology through primary, cell autonomous effects and secondary, non-cell autonomous mechanisms. Identifying these cell type-specific changes and interpreting them in the overall context of the disease have remained difficult, especially in the case of chronic neurodegenerative disorders. As a result, although extensive effort has been invested into studying these processes, effective therapeutic interventions for the majority of neurodegenerative diseases are lacking. The work presented here describes my graduate studies in Dr. Janghoo Lim’s lab, collectively aimed at improving approaches to neurodegenerative diseases through (1) elucidating the molecular mechanisms underlying degeneration of selectively vulnerable neuronal populations, (2) uncovering previously undescribed roles for non-neuronal cells in dysfunction and degeneration of affected tissues, and (3) developing and testing novel therapeutic strategies in pre-clinical animal models of disease. In the first chapter, I comprehensively review the previous literature describing the pathogenic mechanisms underlying spinocerebellar ataxia type 1 (SCA1), which has been focused on Purkinje cells (PCs), a rare cerebellar cell type that degenerates at late stages in the disease. I then introduce a novel framework that extends the analysis of cellular and molecular disease mechanisms beyond a single cell type by dissecting how many cell types within a heterogenous tissue simultaneously contribute to the pathogenesis and progression of a disease. By performing single-nucleus RNA-sequencing of the mouse and human SCA1 cerebellum and constructing continuous dynamic trajectories of each population, we define the unique temporal dynamics of different subsets of cells throughout all stages of disease. Furthermore, we specifically report the precise transcriptional changes that precede loss of PCs and identified early oligodendroglial impairments that can profoundly impact cerebellar function. This work uncovers new roles for diverse cerebellar cell types in SCA1 and provides a generalizable analysis framework for studying the mechanisms underlying the process of neurodegeneration. In the second and third chapters, I introduce two novel functions of Nemo-like kinase (Nlk), a protein previously implicated in several neurodegenerative disorders for its role in phosphorylating the disease-causing proteins. In Chapter 2, I report that Nlk is a negative regulator of lysosome-associated gene transcription, and that its reduction promotes functional lysosome biogenesis in motor neurons of the brain and spinal cord. Furthermore, genetic or pharmacological reduction of Nlk enhanced clearance of aggregated TDP-43 and ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. In Chapter 3, I report that Nlk is also a regulator of receptor-mediated endocytosis and that modulation of endocytosis via reduction of Nlk in microglia, but not neurons, can alter total brain levels of Progranulin (Pgrn), a protein for which haploinsufficiency is causal for frontotemporal lobar degeneration. We demonstrate that Nlk reduction promotes Pgrn degradation by enhancing its trafficking through endocytosis-lysosomal pathway, revealing a new mechanism for Pgrn level regulation in the brain through the active catabolism by microglia. Taken together, this work reveals new roles for different glial cell types in several neurodegenerative disorders and provides insights into the mechanisms regulating protein trafficking and lysosomal function, with broad implications for a variety of protein aggregation disorders.

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