Disrupted Autophagy Leads to Dopaminergic Axon and Dendrite Degeneration and Promotes Presynaptic Accumulation of α-Synuclein and LRRK2 in the Brain
Open accessAbstract
Parkinson's disease (PD) is characterized pathologically by the formation of ubiquitin and α-synuclein (α-syn)-containing inclusions (Lewy bodies), dystrophic dopamine (DA) terminals, and degeneration of midbrain DA neurons. The precise molecular mechanisms underlying these pathological features remain elusive. Accumulating evidence has implicated dysfunctional autophagy, the cell self-digestion and neuroprotective pathway, as one of the pathogenic systems contributing to the development of idiopathic PD. Here we characterize autophagy-deficient mouse models and provide in vivo evidence for the potential role that impaired autophagy plays in pathogenesis associated with PD. Cell-specific deletion of essential autophagy gene Atg7 in midbrain DA neurons causes delayed neurodegeneration, accompanied by late-onset locomotor deficits. In contrast,Atg7-deficient DA neurons in the midbrain exhibit early dendritic and axonal dystrophy, reduced striatal dopamine content, and the formation of somatic and dendritic ubiquitinated inclusions in DA neurons. Furthermore, whole-brain-specific loss of Atg7 leads to presynaptic accumulation of α-syn and LRRK2 proteins, which are encoded by two autosomal dominantly inherited PD-related genes. Our results suggest that disrupted autophagy may be associated with enhanced levels of endogenous α-syn and LRRK2 proteins in vivo. Our findings implicate dysfunctional autophagy as one of the failing cellular mechanisms involved in the pathogenesis of idiopathic PD.
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DA neuron-specific autophagy deficiency leads to restrictive presynaptic accumulation of synuclein in the dorsal striatum.
“Friedman et al.9 demonstrated that DA neuron-specific autophagy deficiency leads to the restrictive presynaptic accumulation of synuclein in the dorsal striatum, suggesting that impaired autophagy plays a role in PD pathogenesis.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [9]
One explanation for the lack of concomitant reductions in DOPAC and HVA may be presynaptic dysfunction in Atg7-deficient mice.
“Until now, we did not clarify the reason, but one of the explanation may be presynaptic dysfunction in Atg7-deficient mice9.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [9]
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Self-citation
- Authors
- Friedman, L. G., Lachenmayer, M. L., Wang, J., He, L., Poulose, S. M., Komatsu, M., Holstein, G. R., & Yue, Z.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-05-30
- Volume
- 32
- Issue
- 22
- Pages
- 7585-7593
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3382107
- OpenAlex
- W2126478464
- Cited by
- 303
- References
- 30
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 18 · 2023: 21 · 2022: 18 · 2021: 23 · 2020: 29 · 2019: 19 · 2018: 22 · 2017: 19 · 2016: 24 · 2015: 20 · 2014: 13 · 2013: 30 · 2012: 12
- FWCI
- 15.68
- 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
- National Science Foundation (9724504, 1 S10 RR0 9145-01)
- Michael J. Fox Foundation for Parkinson's Research
- Bachmann-Strauss Dystonia and Parkinson Foundation
- Parkinson Alliance
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (1S10 RR0 9145-01)
- U.S. Public Health Service (RNS055683A)
- Parkinsonfonden
- National Institute of Mental Health (T32MH096678)
- National Cancer Institute (R24CA095823)
- National Institute of Neurological Disorders and Stroke (R21NS055683, R01NS072359, R01NS060809, NS060809, R01NS060123)
- National Center for Research Resources (1 S10RR0 9145-01)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, autophagy, ATG7, dopaminergic neurons, axonal degeneration, dendritic degeneration, alpha-synuclein, LRRK2, Lewy bodies, midbrain, striatal dopamine, locomotor deficits, neurodegeneration
- MeSH terms
- Autophagy-Related Protein 5, Autophagy-Related Protein 7, Animals, Autophagy, Brain, Cells, Cultured, Inclusion Bodies, Chromatography, High Pressure Liquid, Dendrites, Disease Models, Animal, Dopamine, Embryo, Mammalian, Fibroblasts, Gene Expression Regulation, Intermediate Filament Proteins, Mice, Transgenic, Microtubule-Associated Proteins, Motor Activity, Movement Disorders, Nerve Degeneration, Nerve Tissue Proteins, Tyrosine 3-Monooxygenase, Presynaptic Terminals, Ubiquitin, Ephrin-B1, Mice, alpha-Synuclein, Dopaminergic Neurons, Nestin
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