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Cited by 588Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyLysosomal Storage Disorders Research

Interplay of LRRK2 with chaperone-mediated autophagy

Open access
Orenstein, Samantha J, Kuo, Sheng-Han, Tasset, Inmaculada, Arias, Esperanza, Koga, Hiroshi, Fernandez-Carasa, Irene, Cortes, Etty, Honig, Lawrence S +5 more·2013·Nature Neuroscience
DOI 10.1038/nn.3350PMC PMC3609872
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Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease. We found LRRK2 to be degraded in lysosomes by chaperone-mediated autophagy (CMA), whereas the most common pathogenic mutant form of LRRK2, G2019S, was poorly degraded by this pathway. In contrast to the behavior of typical CMA substrates, lysosomal binding of both wild-type and several pathogenic mutant LRRK2 proteins was enhanced in the presence of other CMA substrates, which interfered with the organization of the CMA translocation complex, resulting in defective CMA. Cells responded to such LRRK2-mediated CMA compromise by increasing levels of the CMA lysosomal receptor, as seen in neuronal cultures and brains of LRRK2 transgenic mice, induced pluripotent stem cell-derived dopaminergic neurons and brains of Parkinson's disease patients with LRRK2 mutations. This newly described LRRK2 self-perpetuating inhibitory effect on CMA could underlie toxicity in Parkinson's disease by compromising the degradation of α-synuclein, another Parkinson's disease-related protein degraded by this pathway.

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  • Mutations in cathepsins D and F lead to NCL.

    “Mutations in several of the cathepsins lead to NCL (D and F), and others have also been identified as risk factors for neurodegenerative disease (B, D, and F).88,122,123”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [122]

    The Discussion addresses LRRK2 mutations and Parkinson’s disease, not cathepsin D or F mutations and NCL. A search for cathepsins in our copy found a reference to cathepsin A, but no passage supporting the attributed claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Cathepsins B, D, and F are risk factors for neurodegenerative disease.

    “Mutations in several of the cathepsins lead to NCL (D and F), and others have also been identified as risk factors for neurodegenerative disease (B, D, and F).88,122,123”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [122]

    The Discussion (page unavailable) addresses LRRK2 and α-synuclein in Parkinson’s disease, not cathepsins B, D, or F as neurodegenerative-disease risk factors. A search for “cathepsin” found only a References entry concerning cathepsin A; searches for the named cathepsins and NCL found no supporting passage in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Orenstein, S. J., Kuo, S.-H., Tasset, I., Arias, E., Koga, H., Fernandez-Carasa, I., Cortes, E., Honig, L. S., Dauer, W., Consiglio, A., Raya, A., Sulzer, D., & Cuervo, A. M.
Affiliations
  • Albert Einstein College of Medicine (US)
  • Columbia University Irving Medical Center (US)
  • University of Michigan (US)
  • Institut de Biomedicina de la Universitat de Barcelona (ES)
Corresponding author
Sulzer, David
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2013-03-03
Volume
16
Issue
4
Pages
394-406
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.3350
PMC
PMC3609872
OpenAlex
W1987155530
Cited by
588
References
6
Citations by year
2026: 14 · 2025: 29 · 2024: 35 · 2023: 33 · 2022: 38 · 2021: 53 · 2020: 53 · 2019: 44 · 2018: 53 · 2017: 54 · 2016: 45 · 2015: 56 · 2014: 47 · 2013: 32
FWCI
38.32
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Michael J. Fox Foundation for Parkinson's Research
  • National Institutes of Health
  • National Institute on Aging (AG08702, R01AG021904, R37AG021904, P01AG031782, P50AG008702, AG031782, P30AG038072, AG038072, T32AG023475)
  • National Institute of Neurological Disorders and Stroke (P50NS038370, K08NS083738)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
LRRK2, chaperone-mediated autophagy, Parkinson's disease, G2019S mutation, alpha-synuclein degradation, lysosomal degradation, dopaminergic neurons, protein aggregation
MeSH terms
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Aged, 80 and over, Animals, Animals, Newborn, Autophagy, Brain Chemistry, Cells, Cultured, Female, Humans, Male, Mice, Transgenic, Middle Aged, Mutation, Protein Binding, Rats, Wistar, Protein Serine-Threonine Kinases, Mice, Knockout, Molecular Chaperones, Mice, Rats, HEK293 Cells

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