Abstract

Brain aging is characterized by a time-dependent decline of tissue integrity and function, and it is a major risk for neurodegenerative diseases and brain cancer. Chaperone-mediated autophagy (CMA) is a selective form of autophagy specialized in protein degradation, which is based on the individual translocation of a cargo protein through the lysosomal membrane. Regulation of processes such as proteostasis, cellular energetics, or immune system activity has been associated with CMA, indicating its pivotal role in tissue homeostasis. Since first studies associating Parkinson’s disease (PD) to CMA dysfunction, increasing evidence points out that CMA is altered in both physiological and pathological brain aging. In this review article, we summarize the current knowledge regarding the impact of CMA during aging in brain physiopathology, highlighting the role of CMA in neurodegenerative diseases and glioblastoma, the most common and aggressive brain tumor in adults.

Highlights

  • TO AUTOPHAGYThe term ‘‘autophagy’’ comes from the Ancient Greek meaning ‘‘self-eating,’’ which refers to the catabolic processes that use the cell to recycle its own constituents within the lysosome (Yang and Klionsky, 2010; Boya et al, 2013)

  • We summarize the current knowledge regarding the impact of chaperone-mediated autophagy’’ (CMA) during aging in brain physiopathology, highlighting the role of CMA in neurodegenerative diseases and glioblastoma, the most common and aggressive brain tumor in adults

  • Selective forms of macroautophagy and microautophagy have been described (Klionsky et al, 2016), with a special interest in ‘‘chaperone-assisted selective autophagy’’ (CASA), which participates in the selective trapping of ubiquitin-positive protein aggregates via autophagosomes (Arndt et al, 2010) and ‘‘endosomal-microautophagy,’’ in which cytosolic proteins enter endosomal compartments inside vesicles generated at the surface of the late endosomes (Sahu et al, 2011)

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Summary

TO AUTOPHAGY

The term ‘‘autophagy’’ comes from the Ancient Greek meaning ‘‘self-eating,’’ which refers to the catabolic processes that use the cell to recycle its own constituents within the lysosome (Yang and Klionsky, 2010; Boya et al, 2013). Further studies demonstrated the existence of another type of autophagy named ‘‘microautophagy,’’ which involves the uptake of soluble or membrane-bound material directly into the lysosome by invagination (De Duve and Wattiaux, 1966; Marzella et al, 1981). It was not until Dice et al (1986) described a proteinselective form of autophagy, identifying a pentapeptide region on ribonuclease A required for its enhanced degradation during serum deprivation. Selective forms of macroautophagy and microautophagy have been described (Klionsky et al, 2016), with a special interest in ‘‘chaperone-assisted selective autophagy’’ (CASA), which participates in the selective trapping of ubiquitin-positive protein aggregates via autophagosomes (Arndt et al, 2010) and ‘‘endosomal-microautophagy,’’ in which cytosolic proteins enter endosomal compartments inside vesicles generated at the surface of the late endosomes (Sahu et al, 2011)

CMA in Aging
Mechanism of Action
Regulation of CMA Function
Crosstalk With Other Types of Protein Degradation Systems
CMA DURING PHYSIOLOGICAL AGING
CMA DURING PHYSIOLOGICAL AGING IN THE BRAIN
Key effector
Human CSF Human neuroblastoma cell line
PHYSIOLOGICAL ROLES OF CMA IN THE BRAIN
Altered Proteostasis
Impaired Cellular Energetics and Metabolism
Augmented Genomic Instability
Cell Cycle Dysregulation and Senescence
Changes in Stem Cell Subpopulation
Immune System Alterations
CMA IN NEURODEGENERATIVE DISEASES
Reduction of the expresion in sporadic PD
Rat ventral midbrain neuronal cultures
CMA substrate CMA substrate
Other Neurodegenerative Disorders
CMA IN GLIOBLASTOMA
THERAPEUTIC TARGETING OF CMA
Findings
CONCLUDING REMARKS AND FUTURE PERSPECTIVES
Full Text
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