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First published online 6 February 2007
doi: 10.1242/jcs.001073

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Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age

Roberta Kiffin^*, Susmita Kaushik^*, Mei Zeng, Urmi Bandyopadhyay, Cong Zhang, Ashish C. Massey, Marta Martinez-Vicente and Ana Maria Cuervo

Department of Anatomy and Structural Biology, Department of Developmental and Molecular Biology and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA

Author for correspondence (e-mail: amcuervo{at}aecom.yu.edu)

Accepted 4 January 2007

Rates of autophagy, the mechanism responsible for lysosomal clearance of cellular components, decrease with age. We have previously described an age-related decline in chaperone-mediated autophagy (CMA), a selective form of autophagy, by which particular cytosolic proteins are delivered to lysosomes after binding to the lysosome-associated membrane protein type 2A (LAMP-2A), a receptor for this pathway. Rates of CMA decrease with age because of a decrease in the levels of LAMP-2A. In this work we have investigated the reasons for the reduced levels of LAMP-2A with age. While transcriptional rates of LAMP-2A remain unchanged with age, the dynamics and stability of the receptor in the lysosomal compartment are altered. The mobilization of the lysosomal lumenal LAMP-2A to the membrane when CMA is activated is altered in lysosomes from old animals, leading to the presence of an unstable pool of lumenal LAMP-2A. By contrast, the regulated cleavage of LAMP-2A at the lysosomal membrane is reduced owing to altered association of the receptor and the protease responsible for its cleavage to particular membrane microdomain regions. We conclude that age-related changes at the lysosomal membrane are responsible for the altered turnover of the CMA receptor in old organisms and the consequent decline in this pathway.

Key words: Aging, Autophagy, Lysosomes, Lysosomal membrane proteins, Proteases, Lipid microdomains

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