All intracellular components are subjected to constant synthesis and degradation which guarantees their continuous renewal. This application focuses on a cellular pathway, known as chaperone-mediated autophagy (CMA), responsible for the selective removal of cytosolic proteins in lysosomes. We have previously identified that the activity of this pathway decreases with age and proposed that declined CMA activity could contribute to the intracellular accumulation of altered proteins characteristic of old organisms. The long-term goal of our study is to understand the cause(s) and consequences of the decrease in CMA activity with age and to restore normal CMA activity in old organisms and analyze the possible beneficial effects of this intervention. We will use in vitro systems with isolated lysosomes and in vivo mouse models with altered or improved CMA activity to: 1) determine the changes in the lysosomal compartment responsible for the observed instability of the receptor for CMA in old organisms;2) identify the signaling mechanisms that regulate CMA activity;3) analyze the systemic consequences of changes in CMA activity with age and the possible beneficial effect of multi-organ preservation of normal CMA activity until advanced ages in life-span and incidence of age-related diseases. The studies proposed in this project should provide the basis for new approaches to restore CMA in old organisms and in pathological conditions with altered activity of this catabolic pathway.

Public Health Relevance

TO PUBLIC HEALTH: The gradual deterioration of the cellular quality control systems is in part responsible for the loss of function and the high incidence of disease as individuals age. Alteration of these systems is on the basis of detrimental metabolic and neurodegenerative disorders, highly prevalent in the aging population, such as diabetes or Alzheimer's disease. Understanding the contribution of alterations in CMA to the poor handling of altered proteins in old organisms is essential for any future efforts to improve functional performance in elders and to delay the onset of age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021904-07
Application #
7609063
Study Section
Special Emphasis Panel (ZRG1-BDA-J (02))
Program Officer
Velazquez, Jose M
Project Start
2003-04-15
Project End
2013-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
7
Fiscal Year
2009
Total Cost
$340,300
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Tekirdag, Kumsal; Cuervo, Ana Maria (2018) Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone. J Biol Chem 293:5414-5424
Kaushik, Susmita; Cuervo, Ana Maria (2018) The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol 19:365-381
Bejarano, Eloy; Murray, John W; Wang, Xintao et al. (2018) Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging. Aging Cell :e12777
Gong, Zhenwei; Tasset, Inmaculada; Diaz, Antonio et al. (2018) Humanin is an endogenous activator of chaperone-mediated autophagy. J Cell Biol 217:635-647
Kaushik, Susmita; Cuervo, Ana Maria (2016) AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. Autophagy 12:432-8
Tasset, Inmaculada; Cuervo, Ana Maria (2016) Role of chaperone-mediated autophagy in metabolism. FEBS J 283:2403-13
Madrigal-Matute, Julio; Cuervo, Ana Maria (2016) Regulation of Liver Metabolism by Autophagy. Gastroenterology 150:328-39
Arias, Esperanza; Koga, Hiroshi; Diaz, Antonio et al. (2015) Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy. Mol Cell 59:270-84
Botbol, Yair; Macian, Fernando (2015) Assays for Monitoring Macroautophagy Activity in T cells. Methods Mol Biol 1343:143-53
Kaushik, Susmita; Cuervo, Ana Maria (2015) Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nat Cell Biol 17:759-70

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