Impairment of the glial phagolysosomal system drives prion-like propagation in aDrosophilamodel of Huntington’s disease

Abstract

Amyloid aggregate accumulation and spread between synaptically-connected regions of the brain is a hallmark of neurodegenerative disease progression. Glia participate in neuropathogenesis by reducing protein aggregate loads via phagocytosis while simultaneously acting as vectors for aggregate spread between cells. Emerging evidence supports the hypothesis that aggregate accumulation compromises the ability of glia to clear toxic material from the brain, possibly by disrupting the phagolysosomal compartment. A better understanding of how glia become deficient in the disease state could reveal novel therapeutic targets. Here, we report that mutant huntingtin (mHTT) aggregates impair glial responsiveness to injury and capacity to degrade axonal debris in aDrosophilamodel of Huntington’s disease (HD). mHTT aggregate formation in neurons slowed engulfment and clearance of injured axons and caused accumulation of late phagosomes and lysosomes in glia. Neuronal mHTT expression induced innate immunity and phagocytic genes, some of which regulated mHTT aggregate burden in the brain. A forward genetic screen targeting glial Rab GTPases revealed Rab10 as a novel modifier of mHTT aggregate transmission from neurons to glia that acts downstream of the phagocytic receptor, Draper. This suggests that Rab-mediated intercellular vesicle sorting mechanisms could create opportunities for prion-like mHTT aggregates to escape lysosomal degradation. Together, our findings support a model in which mHTT aggregate build-up within the phagolysosomal system impairs glial phagocytosis while also promoting the generation of seeding-competent pathological proteins. The new mechanistic information we report here adds to a growing recognition of phagocytic glia as double-edged players in prion-like proteopathies such as HD.SIGNIFICANCE STATEMENTDeposition of amyloid aggregates is closely associated with neurodegenerative disease progression and neuronal death. Recent studies highlight glia as dynamic mediators of disease, capable of phagocytosing dying neurons and amyloid aggregates, while also inducing chronic inflammation and promoting proteopathic spread. Thus, glia have emerged as promising therapeutic targets for disease intervention. Here, we demonstrate in aDrosophilamodel of Huntington’s disease that neuronal mHTT aggregates interfere with glial phagocytic functions, stimulate innate immunity signaling, and impair phagolysosomal processing. We also identify Rab10 as a novel modifier of prion-like transmission of mHTT aggregates, suggesting that Rab-mediated intramembrane fusion in the phagolysosomal system could drive aggregate pathology spread.