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Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) stretch within the Huntingtin (Htt) protein. Pathogenic Htt disrupts multiple neuronal processes, including gene expression, axonal trafficking, proteasome and mitochondrial activity, and intracellular vesicle trafficking. However, the primary pathogenic mechanism and subcellular site of action for mutant Htt are still unclear. Using a Drosophila HD model, we found that pathogenic Htt expression leads to a profound overgrowth of synaptic connections that correlates directly with the levels of Htt at nerve terminals. Branches of the same nerve containing different levels of Htt show distinct phenotypes, indicating that Htt acts locally to disrupt synaptic growth. The effects of pathogenic Htt on synaptic growth arise from defective synaptic endosomal trafficking, leading to expansion of a recycling endosomal signaling compartment containing Sorting Nexin 16 and a reduction in late endosomes containing Rab11. The disruption of endosomal compartments leads to elevated BMP signaling within nerve terminals, driving excessive synaptic growth. Blocking aberrant signaling from endosomes or reducing BMP activity ameliorates the severity of HD pathology and improves viability. Pathogenic Htt is present largely in a nonaggregated form at synapses, indicating that cytosolic forms of the protein are likely to be the toxic species that disrupt endosomal signaling. Our data indicate that pathogenic Htt acts locally at nerve terminals to alter trafficking between endosomal compartments, leading to defects in synaptic structure that correlate with pathogenesis and lethality in the Drosophila HD model. SIGNIFICANCE STATEMENT Huntington's disease (HD) is the most commonly inherited polyglutamine expansion disorder, but how mutant Huntingtin (Htt) disrupts neuronal function is unclear. In particular, it is unknown within what subcellular compartment pathogenic Htt acts and whether the pathogenesis is associated with aggregated or more soluble forms of the protein. Using a Drosophila HD model, we find that nonaggregated pathogenic Htt acts locally at synaptic terminals to disrupt endosomal compartments, leading to aberrant wiring defects. Genetic manipulations to increase endosomal trafficking of synaptic growth receptors from signaling endosomes or to reduce BMP signaling reduce pathology in this HD model. These data indicate that pathogenic Htt can act locally within nerve terminals to disrupt synaptic endosomal signaling and induce neuropathology.

Pathogenic Huntington Alters BMP Signaling and Synaptic Growth through Local Disruptions of Endosomal Compartments