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Role of Chaperone-Mediated Autophagy in Ageing and Neurodegeneration

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Toxicity and Autophagy in Neurodegenerative Disorders

Part of the book series: Current Topics in Neurotoxicity ((Current Topics Neurotoxicity,volume 9))

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Abstract

Depending on the mechanism and molecular players involved in the targeting of a substrate to the lysosome, autophagy can be divided in three different subtypes: Macroautophagy, Microautophagy and Chaperone-Mediated Autophagy (CMA).

In contrast to other forms of autophagy, in CMA, soluble cytosolic proteins can be targeted selectively for degradation in lysosomes. Selectivity in CMA is conferred by the presence of a pentapeptide motif in the amino acid sequence of the substrate proteins, biochemically related to KFERQ, that is recognized by the cytosolic chaperone Hsc70, which results in the targeting of substrates to the lysosome. Once at the lysosomal surface, the substrate–chaperone complex binds to the membrane, and, after unfolding the substrate, is translocated into the lumen by LAMP2A, that acts as the resident a CMA “receptor”.

CMA has been implicated both in the elimination of parts of the proteome damaged by stressors as well as in the selective turnover of substrates directly related with several proteinophaties, most notably in neurodegenerative diseases. In this chapter we will focus on the role of CMA in age-related neurodegeneration and how CMA often becomes the target of the toxic effect of neurodegeneration-related aberrant substrates. The mulfactorial nature of the CMA role in neurodegenerative disorders makes the careful analyses of the evidences gathered thus far instrumental for the understanding of CMA in the context of these diseases.

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Abbreviations

CMA:

Chaperone mediated autophagy

Hsc:

Heat shock cognate protein

LAMP2:

Lysosomal associated protein 2

KDa:

Kilodalton

HSP:

Heat shock protein

Bag:

Bcl 2 associate athanogene

Hop:

Hsc70 Hsp90 organizing protein

Hip:

Hsc70 interacting protein

GFAP:

Glial fibrillary acidic protein

EF1α:

Elongation factor 1 alpha

Lys:

Lysosomal

UPS:

Ubiquitin proteasome system

HD:

Huntinton’s disease

PD:

Parkinson’s disease

RNA:

Ribonucleic Acid

LRRK2:

Leucine rich repeat kinase 2

UCH-L1:

Ubiquitin C terminal hydrolase L1

IPS:

Induced pluripotent stem cells

MEF:

Myocyte enhancer factor

AD:

Alzheimer’s disease

RCAN1:

Regulator of calcineurin 1

HTT:

Huntingtin

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Authors and Affiliations

  1. Faculty of Medicine, Center of Ophthalmology and Vision Sciences, Institute for Biomedical Imaging and Life Science (IBILI), University of Coimbra, 3000-548, Coimbra, Azinhaga de Sta. Comba—Celas, Portugal

    J.V. Ferreira, P. Pereira & H. Girao

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  1. J.V. Ferreira
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  2. P. Pereira
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Correspondence to H. Girao .

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  1. Bioquímica y Biología Molecular y Gen., Facultad de Enfermería y T.O., Cáceres, Spain

    José M. Fuentes

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Ferreira, J., Pereira, P., Girao, H. (2015). Role of Chaperone-Mediated Autophagy in Ageing and Neurodegeneration. In: Fuentes, J. (eds) Toxicity and Autophagy in Neurodegenerative Disorders. Current Topics in Neurotoxicity, vol 9. Springer, Cham. https://doi.org/10.1007/978-3-319-13939-5_2

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