Interplay of LRRK2 with chaperone-mediated autophagy

• Published in: Nature neuroscience Vol. 16; no. 4; pp. 394 - 406
• Main Authors: Orenstein, Samantha J, Kuo, Sheng-Han, Tasset, Inmaculada, Arias, Esperanza, Koga, Hiroshi, Fernandez-Carasa, Irene, Cortes, Etty, Honig, Lawrence S, Dauer, William, Consiglio, Antonella, Raya, Angel, Sulzer, David, Cuervo, Ana Maria
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-04-2013; Nature Publishing Group
• Subjects: 631/378/1689/1718; 631/80/39/2345; 631/80/474; 631/80/474/1624; 692/420/2489/144; Aged, 80 and over; Animal Genetics and Genomics; Animals; Animals, Newborn; Autophagy; Autophagy (Cytology); Autophagy - physiology; Behavioral Sciences; Bioengineering; Biological Techniques; Biomedicine; Brain; Brain Chemistry - genetics; Brain Chemistry - physiology; Cells, Cultured; Experiments; Female; Fibroblasts; Gene mutations; Genetic aspects; HEK293 Cells; Humans; Kinases; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Mice; Mice, Knockout; Mice, Transgenic; Middle Aged; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Mutation; Mutation - physiology; Neurobiology; Neurosciences; Parkinson's disease; Physiological aspects; Protein Binding - physiology; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Rats; Rats, Wistar; Risk factors; Toxicity; United States; Spain; New York; United States > US
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.3350

This study shows that Parkinson's disease–associated mutant forms of leucine-rich repeat kinase 2 (LRRK2) impair chaperone-mediated autophagy in neurons, thereby reducing degradation of α-synuclein by this pathway and contributing to the accumulation of this protein observed in brain tissue from patients with Parkinson's disease.
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.