TY - JOUR
T1 - Interplay of LRRK2 with chaperone-mediated autophagy
AU - Orenstein, Samantha J.
AU - Kuo, Sheng Han
AU - Tasset, Inmaculada
AU - Arias, Esperanza
AU - Koga, Hiroshi
AU - Fernandez-Carasa, Irene
AU - Cortes, Etty
AU - Honig, Lawrence S.
AU - Dauer, William
AU - Consiglio, Antonella
AU - Raya, Angel
AU - Sulzer, David
AU - Cuervo, Ana Maria
N1 - Funding Information:
We thank the Michael J. Fox Foundation for kindly providing some of the LRRK2 antibodies, C. Calatayud for help with neuronal differentiation of iPSC, D. Arduino and B. Caballero for their help with the generation of the LRRK2 knockdown cells, J.P. Vonsattel and R. Alcalay for assistance with human tissue and A. Diaz and B. Patel for technical assistance in several aspects of this work. This work was supported by grants from the US National Institutes of Health National Institute on Aging (AG031782 and AG038072 (A.M.C.) and AG08702 (Alzheimer’s Disease Research Center at Columbia University)), MINECO (SAF2012-33526, PLE2009-0144 and ACI2010-1117 (A.R.); RyC-2008-02772 and BFU2010-21823 (A.C.)), the Beatrice and Roy Backus Foundation (A.M.C.), the Rainwaters Foundation (A.M.C.), a Robert and Renee Belfer gift (A.M.C.), the JPB Foundation (D.S.), the Parkinson’s Disease Foundation (D.S. and S.-H.K.), Fondazione Guido Berlucchi (A.C.), a CIBERNED Cooperative Project (A.R.), a US National Institute of Neurological Disorders and Stroke Udall Center of Excellence (A.M.C. and D.S.) and a Hirschl/ Weill-Caulier Career Scientist Award (A.M.C.). S.J.O. was supported by US National Institutes of Health National Institute on Aging training grant T32AG023475 and S.-H.K. by an American Academy of Neurology Research Fellowship.
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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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U2 - 10.1038/nn.3350
DO - 10.1038/nn.3350
M3 - Article
C2 - 23455607
AN - SCOPUS:84875640261
SN - 1097-6256
VL - 16
SP - 394
EP - 406
JO - Nature neuroscience
JF - Nature neuroscience
IS - 4
ER -