View Program - 63rd Annual Drosophila Research Conference

A key pathological and diagnostic feature of most neurodegenerative diseases is appearance of insoluble aggregates due to protein misfolding in the central nervous system (CNS). Accumulation of toxic protein aggregates in the brain is partially offset by a number of clearance mechanisms, including the ubiquitin-proteasome pathway, autophagy, and engulfment by phagocytic glia. A growing body of evidence supports the hypothesis that pathogenic aggregates associated with many neurodegenerative diseases behave similarly to infectious prions--they spread from cell-to-cell and nucleate the aggregation of natively-folded versions of the same protein, events which are thought to contribute to propagation of aggregates in the brain. We have recently reported that mutant huntingtin (mHTT) aggregates associated with the inherited neurodegenerative disorder Huntington’s disease spread in a “prion-like” manner between synaptically-connected neurons and glia in the Drosophila CNS. mHTT aggregates formed in presynaptic olfactory receptor neuron (ORN) axons directly nucleate the aggregation of soluble wild-type HTT (wtHTT) proteins expressed in post-synaptic partner projection neurons (PNs) or nearby glia. ORN-to-PN and ORN-to-glia transfer of mHTT aggregates is enhanced when ORN activity is silenced, slowed when caspase-dependent apoptosis in ORNs is blocked, and remarkably, require expression of the conserved glial scavenger receptor Draper/MEGF10. Further, mHTT aggregate transmission between synaptically-connected ORNs and PNs requires a transient visit to the glial cytoplasm, indicating that phagocytic glia directly mediate aggregate transfer between neurons in vivo. Preliminary data from our lab indicate that entry of phagocytosed neuronal mHTT aggregates into the glial cytoplasm involves certain Rab GTPases with proposed roles in intracellular vesicle membrane fusion related to phagosome maturation, suggesting that inefficient or incomplete progression of engulfed material in the phagolysosomal system may generate seeding-competent mHTT aggregate species in the glial cytoplasm. In support of this, expression of mHTT in ORNs accelerates age-related decline in glial phagocytic clearance of axonal debris. Together, our findings add to a growing understanding of phagocytic glia as double-edged players in neurodegeneration—these cells clear neurotoxic aggregates, but age- and/or disease-related defects in this process can paradoxically promote aggregate propagation in the brain.

Phagocytic glia mediate prion-like spreading of mutant huntingtin aggregates in Drosophila brains

**Phagocytic glia mediate prion-like spreading of mutant huntingtin aggregates in Drosophila brains**