ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 237 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
237 citing papers in PubMed, 1 synthesis or guideline pooled it, 380 citations in OpenAlex.
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- Huntingtin Aggregate-Responsive Autophagy Gene Circuit Mitigates Disease Pathology in R6/2 Mice.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.The Journal of clinical investigation · 2026Review
- Roles of autophagy in brain homeostasis and disease.Nature neuroscience · 2026Review
- Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation.Cell reports · 2026Article
- Huntingtin polyglutamine expansions misdirect axonal transport by perturbing motor and adaptor recruitment.iScience · 2026Article
- Review
- Lysosomal homeostasis at the crossroads of neurodegeneration.The Journal of clinical investigation · 2026Review
- Huntingtin and its allies at the cortico-striatal synapse.Cell death & disease · 2026Review
- An acyclic nucleic acid-modified siRNA targeting CAG expansions for polyglutamine disease treatment.Molecular therapy. Nucleic acids · 2026Article
- Review
- Genetic suppressor of autophagy defects in huntingtin null cells identified using a mutagenesis screen in Dictyostelium discoideum.BMC molecular and cell biology · 2026Article
- Huntingtin knockdown dysregulates autophagic degradation of Apolipoprotein E.Journal of Huntington's disease · 2026Article
- α2-3-sialylated glycosphingolipids in neuroinflammation, immunity, and programmed cell death: mechanistic evidence and context-dependent regulation: a comprehensive review.Frontiers in immunology · 2026Review
- The Fragile Balance: Autophagy's Role in Neurodegenerative Disease Progression.Current neuropharmacology · 2026Review
- The Rab7-Epg5 and Rab39-ema modules cooperatively position autophagosomes for efficient lysosomal fusions.eLife · 2025Article
- Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.Biomolecules · 2025Review
- Article
- Role of LRRK2 in axonal transport and Parkinson's disease.The Biochemical journal · 2025Review
- Advances in gene and cellular therapeutic approaches for Huntington's disease.Protein & cell · 2025Review
177 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.