Date Approved

2-13-2024

Embargo Period

2-13-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.) in Complex Biological Systems

Department

Biological and Biomedical Sciences

College

College of Science & Mathematics

Advisor

Margaret Pearce, Ph.D.

Committee Member 1

Nathaniel Nucci, Ph.D.

Committee Member 2

Yuanquan Song, Ph.D.

Committee Member 3

Melissa Manners, Ph.D.

Committee Member 4

Kenneth A. Myers, Ph.D.

Committee Member 5

Zachary A. Klase, Ph.D.

Keywords

Drosophila, Glia, Huntington's Disease, phagocytosis, phagolysosome, prion-like propagation

Subject(s)

Nervous system--Degeneration

Disciplines

Biology | Life Sciences | Nervous System Diseases

Abstract

The ability of glia to tightly regulate neuronal health and homeostasis in the CNS is conserved across species. Yet, despite the ability to degrade protein aggregates, glia are vulnerable to the accumulation of neurotoxic amyloid aggregates during neurodegenerative disease progress, and even exacerbate their spread. A developing narrative highlights glia as a double-edged sword in neurodegenerative diseases: initially capable of dynamically responding to amyloid aggregate-ladened dying neurons but also capable of inducing chronic inflammation and creating seeding-competent amyloid oligomers. Thus, uncovering the mechanisms that allow glia to control aggregate deposition while preventing the neurotoxic effects and seed generation is vital for the development of disease-modifying treatments. Here, we report that mutant huntingtin (mHTT) impairs glial clearance of axonal debris in a Drosophila model of Huntington’s disease (HD). Neuronal mHTT buildup impaired engulfment and clearance of injured axons while also accumulating in late phagosomes and lysosomes in glia. We identified Rab10 as a novel modifier of neuronal mHTT aggregate seeding in the glial cytoplasm. Finally, the prion-like propagation of mHTT between neurons and glia is dependent on the phagocytic receptor MEGF10 in a mammalian model of HD. Our findings suggest that dysfunctional processing by the glial phagolysosomal system is a key contributor to the spread of amyloid aggregates during neurodegenerative disease progression.

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