Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease
Open accessAbstract
Continuous turnover of intracellular components by autophagy is necessary to preserve cellular homeostasis in all tissues. Alterations in macroautophagy, the main process responsible for bulk autophagic degradation, have been proposed to contribute to pathogenesis in Huntington's disease (HD), a genetic neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin protein. However, the precise mechanism behind macroautophagy malfunction in HD is poorly understood. In this work, using cellular and mouse models of HD and cells from humans with HD, we have identified a primary defect in the ability of autophagic vacuoles to recognize cytosolic cargo in HD cells. Autophagic vacuoles form at normal or even enhanced rates in HD cells and are adequately eliminated by lysosomes, but they fail to efficiently trap cytosolic cargo in their lumen. We propose that inefficient engulfment of cytosolic components by autophagosomes is responsible for their slower turnover, functional decay and accumulation inside HD cells.
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PolyQ-HTT impairs protein clearance pathways and disrupts autophagy by impairing lysosomal degradation and cargo recognition.
“Beyond aggregation, polyQ-HTT impairs protein clearance pathways, exacerbating cellular dysfunction, and disrupts autophagy by impairing lysosomal degradation and cargo recognition [190].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [190]
The Results (‘Autophagosome clearance is not altered in HD’) report preserved clearance by lysosomes and argue against a primary defect in lysosomal proteolysis. The Discussion identifies failed cargo sequestration as the main defect, rather than degradation in the lysosomal compartment. Thus the cargo-recognition part is supported, but the claim that impaired lysosomal degradation is a cause of the autophagy defect is contrary to the paper’s findings. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredMultiple neurodegenerative diseases have dysfunctional mitophagic processes in neurons, as described in Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease.
“Multiple neurodegenerative diseases have dysfunctional mitophagic processes in neurons, as described in Parkinson’s disease (PD) (16), Huntington’s disease (17), amyotrophic lateral sclerosis (ALS) (18), and Alzheimer’s disease (AD) (19,20).”
From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [17]
Autophagy substrates including p62, lipid droplets, and damaged mitochondria accumulated in Tsc2+/- primary neuronal cultures.
“4) an accumulation of autophagy substrates, including p62 (Komatsu et al., 2007a), lipid droplets and damaged mitochondria (Martinez-Vicente et al., 2010), in Tsc2+/- primary neuronal cultures (Figs S5 B, C, D, E);”
From Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits (2014) · cites this paper as Martinez-Vicente et al., 2010
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- Authors
- Martinez-Vicente, M., Talloczy, Z., Wong, E., Tang, G., Koga, H., Kaushik, S., de Vries, R., Arias, E., Harris, S., Sulzer, D., & Cuervo, A. M.
- Affiliations
- Albert Einstein College of Medicine (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Sulzer, David
- Venue
- Nature Neuroscience
- Published
- 2010-04-11
- Volume
- 13
- Issue
- 5
- Pages
- 567-576
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2860687
- OpenAlex
- W2129447571
- Cited by
- 885
- References
- 45
- Citations by year
- 2026: 37 · 2025: 53 · 2024: 40 · 2023: 53 · 2022: 49 · 2021: 70 · 2020: 68 · 2019: 58 · 2018: 69 · 2017: 53 · 2016: 47 · 2015: 58 · 2014: 59 · 2013: 47 · 2012: 56
- FWCI
- 22.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG021904, R37AG021904, P01AG031782, AG-021904, AG031782, T32AG023475)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK041918, P01DK041918)
- National Institute of Neurological Disorders and Stroke (P50NS038370)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- Huntington's disease, autophagy, cargo recognition, autophagosome formation, autophagosome degradation, lysosomal clearance, neurodegeneration, striatal neurons
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Disease Models, Animal, Enzyme Inhibitors, Humans, Huntington Disease, Immunosuppressive Agents, Lysosomes, Mice, Transgenic, Microtubule-Associated Proteins, Mitochondria, Nerve Tissue Proteins, Neurons, Peptides, Subcellular Fractions, Time Factors, Vinca Alkaloids, Apoptosis, Thapsigargin, Sirolimus, Hepatocytes, Serum, Microscopy, Electron, Transmission, Serotonin Plasma Membrane Transport Proteins, Mice
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