Induction of Autophagy in Axonal Dystrophy and Degeneration
Open accessAbstract
Autophagy is a highly regulated cellular mechanism for the bulk degradation of cytoplasmic contents. It has been implicated in a variety of physiological and pathological conditions relevant to neurological diseases. However, the regulation of autophagy in neurons and its role in neuronal and axonal pathology are not yet understood. Using transgenic mice producing green fluorescent protein-tagged autophagic marker microtubule-associated protein light chain 3 (GFP–LC3), we provide molecular evidence for the induction of autophagy in axonal dystrophy and degeneration in Purkinje cells of the Lurcher mice, a model for excitotoxic neurodegeneration. We show that the excitotoxic insult of Lurcher mutation triggers an early response of Purkinje cells involving accumulation of GFP–LC3-labeled autophagosomes in axonal dystrophic swellings (a hallmark of CNS axonopathy). In brain, LC3 interacts with high affinity with the microtubule-associated protein 1B (MAP1B). We show that MAP1B binds to LC3 of both cytosolic form (LC3I) and lipidated form (LC3II). Moreover, in cell culture, overexpression of MAP1B results in reduced LC3II levels and number of GFP–LC3-labeled autophagosomes; phosphorylated MAP1B is associated with GFP–LC3-labeled autophagosomes. Furthermore, in brain, phosphorylated MAP1B accumulates in axonal dystrophic swellings of degenerating Purkinje cells and binds to LC3 at increased level. Therefore, the MAP1B–LC3 interaction may participate in regulation of LC3-associated autophagosomes in neurons, in particular at axons, under normal and pathogenic conditions. We propose that induction of autophagy serves as an early stress response in axonal dystrophy and may participate in the remodeling of axon structures.
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Purkinje cell degeneration models such as pcd mice display motor abnormalities that were similar to those observed in B6.Clec16aGT/GT and Clec16aCURT/CURT mice.
“Purkinje cell degeneration models such as pcd mice display motor abnormalities that were similar to those observed in B6.Clec16aGT/GT and Clec16aCURT/CURT mice3031 and staining with the Purkinje cell marker calbindin confirmed loss of these cells in B6.Clec16aGT/GT mice (Fig. 2d) at 8 weeks of age that was dramatically increased by 47 weeks of age (Supplementary Fig. 2e).”
From Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival (2016) · cites this paper as [31]
The Introduction describes Purkinje cell degeneration in Lurcher mice, and the Methods identify ataxia as a Lurcher phenotype. The paper studies Lurcher mice, not pcd mice, and does not compare their motor abnormalities with those of either Clec16a strain. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAutophagy is necessary for maintaining the structural integrity of the axon.
“Autophagy is also necessary for maintaining the structural integrity of the axon [375]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [375]
Autophagy can accentuate axon degeneration during excitotoxic stress.
“but can also accentuate axon degeneration during excitotoxic stress [375].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [375]
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“eliminate synapses during development [377,378], but can also accentuate axon degeneration during excitotoxic stress [375].”
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- Authors
- Wang, Q. J., Ding, Y., Kohtz, S., Mizushima, N., Cristea, I. M., Rout, M. P., Chait, B. T., Zhong, Y., Heintz, N., & Yue, Z.
- Affiliations
- Tokyo Metropolitan Institute of Medical Science (JP)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-08-02
- Volume
- 26
- Issue
- 31
- Pages
- 8057-8068
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6673783
- OpenAlex
- W2149332763
- Cited by
- 308
- References
- 46
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 14 · 2022: 7 · 2021: 11 · 2020: 10 · 2019: 14 · 2018: 7 · 2017: 15 · 2016: 19 · 2015: 20 · 2014: 24 · 2013: 20 · 2012: 26
- FWCI
- 15.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (RR00862, RR022220)
- U.S. Public Health Service (RNS055683A)
- National Cancer Institute (R33CA089810, CA 89810)
- National Institute of General Medical Sciences (R01GM062427, GM062427)
- National Center for Research Resources (RR00862, P41RR000862, RR 022220, U54RR022220)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- autophagy, axonal dystrophy, axonal degeneration, axonopathy, Purkinje cells, excitotoxic neurodegeneration, MAP1B, LC3, autophagosomes, axonal swellings, neuronal stress response, axon remodeling
- MeSH terms
- Animals, Autophagy, Axons, Cells, Cultured, Mice, Neurologic Mutants, Mice, Transgenic, Nerve Degeneration, Phagosomes, Purkinje Cells, Retrograde Degeneration, Mice
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