Impact of Chaperone-Mediated Autophagy in Brain Aging: Neurodegenerative Diseases and Glioblastoma

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.

Keywords: CMA; LAMP2; glioblastoma; neurodegenerative diseases; physiological aging.

Figure 1

General scheme of the chaperone-mediated autophagy (CMA) process. (1) The KFERQ-like motif of a cargo protein is detected by HSC70, (2) which is the one targeting it into the lysosomal membrane protein lysosome-associated membrane protein type 2A (LAMP2A). Then, (3) LAMP2A monomers are assembled into multimeric structures, forming the translocation complex. Once this structure is correctly formed, (4) protein is translocated through the lysosomal membrane, while lysosomal HSC70 (lys-HSC70) pulls it into the lumen and avoid the return out of the membrane. Lysosomal HSP90 (lys-HSP90) is important in LAMP2A stabilization since it masks lysosomal protease binding sequences, and thus, prevents its degradation during this transition. Finally, (5) protein is degraded inside the lysosome, and (6) translocation complex is disassembled.

Figure 2

Main levels of regulation of CMA. (1) LAMP2A de novo expression can be regulated by the binding of NFAT1 to the promoter of LAMP2 gene, binding of NRF2 and PI3K/AKT/mTOR pathway; (2) LAMP2A trafficking into the lysosomal membrane is altered by cystinosin and Rab11 and RILP protein dysfunctions; (3) in resting conditions, LAMP2A monomers are located in lipid microdomains, where LAMP2A is more sensitive to cathepsin A-mediated degradation. SNX-10 deficiency upregulates LAMP2A expression, probably by dysregulation of cathepsin A trafficking into the lysosomes; (4) Rac1/PHLPP1 complex inhibits Akt, enabling glial fibrillary acidic protein (GFAP)-mediated translocation complex stabilization. On the contrary, this complex is destabilized by GTP-mediated release of Elongation factor 1α (EF1α) from the lysosomal membrane and mTORC2/Akt phosphorylation of GFAP, promoting GFAP self-association. Humanin, a mitochondria-associated peptide, interacts with HSP90 and stabilizes the binding of this chaperone to CMA substrates; (5) recent studies demonstrate that METT21c and potentially HDAC10 regulate HSC70 action by post-transcriptional regulation. HDAC6 regulates HSP90 acetylation and activity.

Figure 3

Current knowledge regarding CMA regulators alteration in brain aging, neurodegenerative diseases, and glioblastoma. Comparison of the pieces of evidence among these three physiopathological conditions of the brain, highlighting the unexplored fields. CSF, cerebrospinal fluid; nNOS, neuronal nitric oxide synthase; PBMC, peripheral blood mononuclear cell.

Figure 4

Common hallmarks of aging and cancer regulated by CMA. Recent evidence demonstrates that physiological aging and ND are associated with CMA downregulation, whereas glioblastoma (GBM) presents an upregulated activity. Processes regulated by CMA are represented in the figure. ND, neurodegenerative diseases.