Interplay of LRRK2 with chaperone-mediated autophagy

Samantha J. Orenstein, Sheng Han Kuo, Inmaculada Tasset, Esperanza Arias-Perez, Hiroshi Koga, Irene Fernandez-Carasa, Etty Cortes, Lawrence S. Honig, William Dauer, Antonella Consiglio, Angel Raya, David Sulzer, Ana Maria Cuervo

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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.

Original languageEnglish (US)
Pages (from-to)394-406
Number of pages13
JournalNature Neuroscience
Volume16
Issue number4
DOIs
StatePublished - Apr 2013

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Autophagy
Leucine
Phosphotransferases
Parkinson Disease
Synucleins
Induced Pluripotent Stem Cells
Mutation
Dopaminergic Neurons
Brain Diseases
Lysosomes
Protein Kinases
Transgenic Mice
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Interplay of LRRK2 with chaperone-mediated autophagy. / Orenstein, Samantha J.; Kuo, Sheng Han; Tasset, Inmaculada; Arias-Perez, Esperanza; Koga, Hiroshi; Fernandez-Carasa, Irene; Cortes, Etty; Honig, Lawrence S.; Dauer, William; Consiglio, Antonella; Raya, Angel; Sulzer, David; Cuervo, Ana Maria.

In: Nature Neuroscience, Vol. 16, No. 4, 04.2013, p. 394-406.

Research output: Contribution to journalArticle

Orenstein, SJ, Kuo, SH, Tasset, I, Arias-Perez, E, Koga, H, Fernandez-Carasa, I, Cortes, E, Honig, LS, Dauer, W, Consiglio, A, Raya, A, Sulzer, D & Cuervo, AM 2013, 'Interplay of LRRK2 with chaperone-mediated autophagy', Nature Neuroscience, vol. 16, no. 4, pp. 394-406. https://doi.org/10.1038/nn.3350
Orenstein, Samantha J. ; Kuo, Sheng Han ; Tasset, Inmaculada ; Arias-Perez, Esperanza ; Koga, Hiroshi ; Fernandez-Carasa, Irene ; Cortes, Etty ; Honig, Lawrence S. ; Dauer, William ; Consiglio, Antonella ; Raya, Angel ; Sulzer, David ; Cuervo, Ana Maria. / Interplay of LRRK2 with chaperone-mediated autophagy. In: Nature Neuroscience. 2013 ; Vol. 16, No. 4. pp. 394-406.
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