Rates of protein degradation decrease with age contributing to abnormal accumulation of proteins in tissues and possible loss of function. We have previously found that the activity of chaperone mediated autophagy (CMA), a selective mechanism for the degradation of cytosolic proteins in lysosomes, declines with age. CMA is preferentially activated during stress and can account for as much as 30% of total protein degradation. Reduced CMA with age could contribute to the accumulation of abnormal proteins in the cytosol of senescent cells, as well as to the impaired ability of these cells to adapt to stress conditions. The limiting step for CMA is the binding of substrate proteins to a receptor at the lysosomal membrane, the lysosome membrane associated protein type 2a (lamp2a). We have found that levels of this receptor are reduced in lysosomes from old rodents and senescent cells. We now propose to elucidate the physiological consequences of the age-related reduction of CMA and to determine whether restoration of CMA activity can revert these abnormalities. We intend to answer the following questions: Why do the receptor levels decrease with age? What are the consequences of reduced CMA? Is it possible to correct impaired CMA by augmenting levels of the receptor in old animals? To address these questions we will: 1) Determine how the levels of the receptor are regulated under different cellular conditions; 2) Inhibit CMA in cultured cells and analyze the cellular consequences; 3) Characterize the changes with age in CMA in a transgenic mouse generated in our laboratory in which the levels of lamp2a can be regulated. If we successfully restore CMA in the old members of this mouse colony we will analyze possible beneficial effects in accumulated aberrant proteins and in the response to stress of these animals. If only a partial restoration is attained, we will combine in the future similar restorative attempts for any other defective component(s) identified through this project.
| 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 |
| Schneider, Jaime L; Villarroya, Joan; Diaz-Carretero, Antonio et al. (2015) Loss of hepatic chaperone-mediated autophagy accelerates proteostasis failure in aging. Aging Cell 14:249-64 |
| Park, Caroline; Suh, Yousin; Cuervo, Ana Maria (2015) Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage. Nat Commun 6:6823 |
| Arias, Esperanza; Koga, Hiroshi; Diaz, Antonio et al. (2015) Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy. Mol Cell 59:270-84 |
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