Chaperone-Mediated Autophagy and Its Implications for Neurodegeneration and Cancer

Abstract

Proteostasis, also known as protein homeostasis, is critical for cell survival. Autophagy is a cellular process that degrades and recycles damaged or long-lived proteins, misfolded proteins, and damaged or abnormal organelles in order to preserve homeostasis. Among the three forms of autophagy, chaperone-mediated autophagy (CMA) is distinct from macroautophagy and microautophagy; it does not require the formation of vacuoles and only degrades selected individual proteins. CMA helps to maintain cellular homeostasis by regulating protein quality, bioenergetics, and substrate-associated cellular processes at the right moment. This pathway’s dysfunction has been linked to several diseases and disorders. Neurodegenerative diseases and cancer have received the most attention. In various neurodegenerative disorders, especially in their later stages, CMA activity declines. CMA has been shown to act as a tumor suppressor in cancer by destroying specific tumor promoters. Once a tumor has grown, it also helps tumor survival and the metastatic cascade. The presence of changes in CMA in these diseases disorders raises the idea of targeting CMA to restore cellular homeostasis as a potential therapeutic method. Manipulation of CMA activity may be effective therapeutic strategies for treating these diseases. Therefore, in this paper; we introduce the basic processes, regulatory mechanisms, and physiological functions of CMA; evidences supporting the role of impaired CMA function in neurodegeneration and cancer; and the potential of how targeting CMA could be a promising therapeutic method for the two diseases.

The role of chaperone-mediated autophagy in drug resistance

“…Also, the mTORC2/AKT1/PHLPP1 axis coordinates the dynamic assembly and disassembly of LAMP2A into multimers, through the phosphatase PHLPP1 inhibition of mTORC2 function, thereby blocking the activation of AKT and promoting the formation of LAMP2A multimers ( Arias et al, 2015 ). Finally, a lysosome-associated form of the GFAP (glial fibrillary acidic protein) and EF1α (elongation factor 1α) also modulated CMA activity in response to oxidative stress ( Assaye and Gizaw, 2022 ).…”

Modulation of Tau Pathology in Alzheimer’s Disease by Dietary Bioactive Compounds

“…Molecular chaperones play important roles in regulating protein homeostasis by promoting proper protein folding and targeting misfolded proteins for lysosomal and UPS-dependent degradation [161,162]. In aged mice overexpressing human tau, curcumin treatment restores the reduction of molecular chaperones heat shock protein (HSP) 90 and heat shock cognate protein (HSC) 70/HSP70 in membrane-enriched fractions while decreasing the soluble tau dimers.…”

Autophagy in Crohn’s Disease: Converging on Dysfunctional Innate Immunity

“…Atypical CMA is less well understood than constitutive and induced CMA, but it is thought to play a role in the turnover of specific proteins, such as those involved in synaptic transmission [ 94 ]. Dysregulation of microphagy or CMA have been implicated in various diseases, including neurodegenerative disorders and cancer [ 95 , 96 ], but have not yet been implicated in IBD.…”