Journal of Shanghai Jiao Tong University (Medical Science) >

2021 , Vol. 41 >Issue 11: 1529 - 1534

DOI: https://doi.org/10.3969/j.issn.1674-8115.2021.11.020

Review

Research progress of chaperone-mediated autophagy in Alzheimer's disease

  • Jun-hui CHEN ,
  • You-quan GU ,
  • Li-he YAO ,
  • Wei ZHANG ,
  • Huai-xiang WANG
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  • 1.Department of Neurology, The First Hospital of Lanzhou University, Lanzhou 730013, China
    2.The First School of Clinical Medicine of Lanzhou University, Lanzhou 730013, China
    3.Department of Stomatology, Lanzhou University Second Hospital, Lanzhou 730030, China
    4.Department of Intensive Care Unit, Ganzhou District People's Hospital of Zhangye City, Gansu Province, Zhangye 734000, China
GU You-quan, E-mail: Guyq@lzu.edu.cn.

Online published: 2021-12-03

Supported by

Natural Science Foundation of Gansu Province(20JR10RA671);Youth Science and Technology Foundation of Gansu Province(21JR1RA152)

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Abstract

Alzheimer's disease (AD) is a common neurodegenerative disease. Its main pathological change is senile plaque (SP) formed by massive accumulation of amyloid β-protein (Aβ) and neurofibrillary tangles (NFTs) formed by excessive phosphorylation and accumulation of Tau protein in cells. Chaperone-mediated autophagy (CMA) selectively transfers proteins with CMA motifs to lysosomes for degradation. When the autophagy process is impaired, Aβ and abnormal phosphorylated Tau protein will accumulate in neurons, which can destroy the normal function of cells and accelerate their death. Relevant studies have shown that CMA is an important pathway for abnormal protein degradation in early AD, and the inactivation of this pathway may play an important role in the progression of AD. This paper reviews the concept, and physiological role of CMA and the pathological relationship between CMA and AD, and elaborates the role of inactivation of CMA pathway in AD diseases, in order to provide new ideas for the research and treatment of AD pathogenesis.

Key words： chaperone-mediated autophagy (CMA); Alzheimer's disease (AD); Tau protein; amyloid β-protein (Aβ)

Cite this article

Jun-hui CHEN , You-quan GU , Li-he YAO , Wei ZHANG , Huai-xiang WANG . Research progress of chaperone-mediated autophagy in Alzheimer's disease[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2021 , 41(11) : 1529 -1534 . DOI: 10.3969/j.issn.1674-8115.2021.11.020

References

1 Galzitskaya O. New mechanism of amyloid fibril formation[J]. Curr Protein Pept Sci, 2019, 20(6): 630-640.
2 P?r?coveanu DFV, Pirici I, Tudoric? V, et al. Tau protein in neurodegenerative diseases: a review[J]. Rom J Morphol Embryol, 2017, 58(4): 1141-1150.
3 Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care[J]. Lancet, 2017, 390(10113): 2673-2734.
4 Guo F, Liu X, Cai H, et al. Autophagy in neurodegenerative diseases: pathogenesis and therapy[J]. Brain Pathol, 2018, 28(1): 3-13.
5 Bourdenx M, Martín-Segura A, Scrivo A, et al. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome[J]. Cell, 2021, 184(10): 2696-2714.e25.
6 Caballero B, Bourdenx M, Luengo E, et al. Acetylated Tau inhibits chaperone-mediated autophagy and promotes Tau pathology propagation in mice[J]. Nat Commun, 2021, 12(1): 2238.
7 Endicott SJ, Boynton DN, Beckmann LJ, et al. Long-lived mice with reduced growth hormone signaling have a constitutive upregulation of hepatic chaperone-mediated autophagy[J]. Autophagy, 2021, 17(3): 612-625.
8 Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy[J]. Nat Rev Mol Cell Biol, 2018, 19(6): 365-381.
9 Wang G, Mao Z. Chaperone-mediated autophagy: roles in neurodegeneration[J]. Transl Neurodegener, 2014, 3: 20.
10 Rothenberg C, Srinivasan D, Mah L, et al. Ubiquilin functions in autophagy and is degraded by chaperone-mediated autophagy[J]. Hum Mol Genet, 2010, 19(16): 3219-3232.
11 Alfaro IE, Albornoz A, Molina A, et al. Chaperone mediated autophagy in the crosstalk of neurodegenerative diseases and metabolic disorders[J]. Front Endocrinol (Lausanne), 2018, 9: 778.
12 Stricher F, Macri C, Ruff M, et al. HSPA8/HSC70 chaperone protein: structure, function, and chemical targeting[J]. Autophagy, 2013, 9(12): 1937-1954.
13 Cuervo AM, Dice JF. Unique properties of lamp2a compared to other lamp2 isoforms[J]. J Cell Sci, 2000, 113(24): 4441-4450.
14 Dice JF. Peptide sequences that target cytosolic proteins for lysosomal proteolysis[J]. Trends Biochem Sci, 1990, 15(8): 305-309.
15 Kim S, Violette CJ, Ziff EB. Reduction of increased calcineurin activity rescues impaired homeostatic synaptic plasticity in presenilin 1 M146V mutant[J]. Neurobiol Aging, 2015, 36(12): 3239-3246.
16 Bandyopadhyay U, Sridhar S, Kaushik S, et al. Identification of regulators of chaperone-mediated autophagy[J]. Mol Cell, 2010, 39(4): 535-547.
17 Kiffin R, Christian C, Knecht E, et al. Activation of chaperone-mediated autophagy during oxidative stress[J]. Mol Biol Cell, 2004, 15(11): 4829-4840.
18 Majeski AE, Dice JF. Mechanisms of chaperone-mediated autophagy[J]. Int J Biochem Cell Biol, 2004, 36(12): 2435-2444.
19 Cuervo AM, Hildebrand H, Bomhard EM, et al. Direct lysosomal uptake of alpha 2-microglobulin contributes to chemically induced nephropathy[J]. Kidney Int, 1999, 55(2): 529-545.
20 Schneider JL, Suh Y, Cuervo AM. Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation[J]. Cell Metab, 2014, 20(3): 417-432.
21 Lv L, Li D, Zhao D, et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth[J]. Mol Cell, 2011, 42(6): 719-730.
22 Aniento F, Roche E, Cuervo AM, et al. Uptake and degradation of glyceraldehyde-3-phosphate dehydrogenase by rat liver lysosomes[J]. J Biol Chem, 1993, 268(14): 10463-10470.
23 Fernández LP, Ramos-Ruiz R, Herranz J, et al. The transcriptional and mutational landscapes of lipid metabolism-related genes in colon cancer[J]. Oncotarget, 2018, 9(5): 5919-5930.
24 Yang Q, Mao Z. The complexity in regulation of MEF2D by chaperone-mediated autophagy[J]. Autophagy, 2009, 5(7): 1073-1074.
25 Park JS, Kim DH, Yoon SY. Regulation of amyloid precursor protein processing by its KFERQ motif[J]. BMB Rep, 2016, 49(6): 337-342.
26 Dou J, Su P, Xu C, et al. Targeting Hsc70-based autophagy to eliminate amyloid β oligomers[J]. Biochem Biophys Res Commun, 2020, 524(4): 923-928.
27 Liu H, Wang P, Song W, et al. Degradation of regulator of calcineurin 1 (RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways[J]. FASEB J, 2009, 23(10): 3383-3392.
28 Wang Y, Martinez-Vicente M, Krüger U, et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing[J]. Hum Mol Genet, 2009, 18(21): 4153-4170.
29 Furman JL, Sompol P, Kraner SD, et al. Blockade of astrocytic calcineurin/NFAT signaling helps to normalize hippocampal synaptic function and plasticity in a rat model of traumatic brain injury[J]. J Neurosci, 2016, 36(5): 1502-1515.
30 Sun X, Wu Y, Herculano B, et al. RCAN1 overexpression exacerbates calcium overloading-induced neuronal apoptosis[J]. PLoS One, 2014, 9(4): e95471.
31 Cook CN, Hejna MJ, Magnuson DJ, et al. Expression of calcipressin1, an inhibitor of the phosphatase calcineurin, is altered with aging and Alzheimer's disease[J]. J Alzheimer's Dis, 2005, 8(1): 63-73.
32 Blanchard JW, Bula M, Davila-Velderrain J, et al. Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes[J]. Nat Med, 2020, 26(6): 952-963.
33 Wang YX, Yang RY, Gu JL, et al. Cross talk between PI3K-AKT-GSK-3β and PP2A pathways determines Tau hyperphosphorylation[J]. Neurobiol Aging, 2015, 36(1): 188-200.
34 Kimura T, Ishiguro K, Hisanaga S. Physiological and pathological phosphorylation of Tau by CDK5[J]. Front Mol Neurosci, 2014, 7: 65.
35 Caballero B, Wang YP, Diaz A, et al. Interplay of pathogenic forms of human Tau with different autophagic pathways[J]. Aging Cell, 2018, 17(1): e12692.
36 Silva MC, Nandi GA, Tentarelli S, et al. Prolonged Tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons[J]. Nat Commun, 2020, 11(1): 3258.
37 Shin MK, Vázquez-Rosa E, Koh Y, et al. Reducing acetylated Tau is neuroprotective in brain injury[J]. Cell, 2021, 184(10): 2715-2732.e23.
38 Arias E, Koga H, Diaz A, et al. Lysosomal mTORC2/PHLPP1/AKT regulate chaperone-mediated autophagy[J]. Mol Cell, 2015, 59(2): 270-284.
39 Tang FL, Erion JR, Tian Y, et al. VPS35 in dopamine neurons is required for endosome-to-Golgi retrieval of Lamp2a, a receptor of chaperone-mediated autophagy that is critical for α-synuclein degradation and prevention of pathogenesis of Parkinson's disease[J]. J Neurosci, 2015, 35(29): 10613-10628.
40 Eckstein LA, Van Quill KR, Bui SK, et al. Cyclosporin a inhibits calcineurin/nuclear factor of activated T-cells signaling and induces apoptosis in retinoblastoma cells[J]. Invest Ophthalmol Vis Sci, 2005, 46(3): 782-790.
41 Else H. The science events to watch for in 2021[J]. Nature, 2021, 589(7840): 14-15.
42 Vaz M, Silvestre S. Alzheimer's disease: recent treatment strategies[J]. Eur J Pharmacol, 2020, 887: 173554.
43 Novak P, Schmidt R, Kontsekova E, et al. Safety and immunogenicity of the Tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial[J]. Lancet Neurol, 2017, 16(2): 123-134.
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