RRC ID 28691
Author Wong YC, Holzbaur EL.
Title The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation.
Journal J Neurosci
Abstract Autophagy is an essential cellular pathway for degrading defective organelles and aggregated proteins. Defects in autophagy have been implicated in the neurodegenerative disorder Huntington's disease (HD), in which polyglutamine-expanded huntingtin (polyQ-htt) is predominantly cleared by autophagy. In neurons, autophagosomes form constitutively at the axon tip and undergo robust retrograde axonal transport toward the cell body, but the factors regulating autophagosome dynamics and autophagosome maturation are not well understood. Here, we show that both huntingtin (htt) and its adaptor protein huntingtin-associated protein-1 (HAP1) copurify and colocalize with autophagosomes in neurons. We use live-cell imaging and RNAi in primary neurons from GFP-LC3 transgenic mice to show that htt and HAP1 control autophagosome dynamics, regulating dynein and kinesin motors to promote processive transport. Expression of polyQ-htt in either primary neurons or striatal cells from HD knock-in mice is sufficient to disrupt the axonal transport of autophagosomes. Htt is not required for autophagosome formation or cargo loading. However, the defective autophagosome transport observed in both htt-depleted neurons and polyQ-htt-expressing neurons is correlated with inefficient degradation of engulfed mitochondrial fragments. Together, these studies identify htt and HAP1 as regulators of autophagosome transport in neurons and suggest that misregulation of autophagosome transport in HD leads to inefficient autophagosome maturation, potentially due to inhibition of autophagosome/lysosome fusion along the axon. The resulting defective clearance of both polyQ-htt aggregates and dysfunctional mitochondria by neuronal autophagosomes may contribute to neurodegeneration and cell death in HD.
Volume 34(4)
Pages 1293-305
Published 2014-1-22
DOI 10.1523/JNEUROSCI.1870-13.2014
PII 34/4/1293
PMID 24453320
PMC PMC3898289
MeSH Animals Autophagy / physiology* Axonal Transport / physiology Disease Models, Animal Female Fluorescent Antibody Technique Gene Knock-In Techniques Huntingtin Protein Huntington Disease / genetics Huntington Disease / metabolism* Huntington Disease / physiopathology Immunoprecipitation Male Mice Mice, Transgenic Mutation Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism* Nuclear Proteins / genetics Nuclear Proteins / metabolism* Phagosomes / genetics Phagosomes / metabolism*
IF 5.674
Times Cited 157
Mice RBRC00806