Pathogenic Huntington Alters BMP Signaling and Synaptic Growth through Local Disruptions of Endosomal Compartments
Author(s)
Akbergenova, Yulia; Littleton, J. Troy
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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.
Date issued
2017-03Department
Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences; Picower Institute for Learning and MemoryJournal
The Journal of Neuroscience
Publisher
Society for Neuroscience
Citation
Akbergenova, Yulia, and Littleton, J. Troy. “Pathogenic Huntington Alters BMP Signaling and Synaptic Growth through Local Disruptions of Endosomal Compartments.” The Journal of Neuroscience 37, 12 (February 2017): 3425–3439 © 2017 The Authors
Version: Final published version
ISSN
0270-6474
1529-2401