Date Approved


Embargo Period


Document Type


Degree Name

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


Biological and Biomedical Sciences


College of Science & Mathematics


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.


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


Nervous system--Degeneration


Biology | Life Sciences | Nervous System Diseases


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.