Malfunctioning of Chaperone-Mediated Autophagy in Parkinson’s Disease: Feats, Constraints, and Flaws of Modulators
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Homeostatic regulation of class II programmed cell death/autophagy for the degradation and elimination of substandard organelles and defective proteins is decisive for the survival of dopaminergic neurons. Chaperone-mediated autophagy (CMA), one of the most highly dedicated self-sacrificing events, is accountable for the partial elimination of redundant soluble cytoplasmic proteins in Parkinson’s disease (PD). CMA is characterized by the selective delivery of superfluous protein containing lysine-phenylalanine-glutamate-arginine-glutamine (KFERQ)/KFERQ-like motif to the lysosome through molecular chaperones, such as heat shock cognate-70 (Hsc-70). KFERQ/KFERQ-like motif present in the poor quality cytoplasmic substrate protein and Hsc-70 complex is recognized by a janitor protein, which is referred to as the lysosome-associated membrane protein-2A (LAMP-2A). This protein is known to facilitate an entry of substrate-chaperone complex in the lumen for hydrolytic cleavage of substrate and elimination of end-products. Impaired CMA is repeatedly blamed for an accumulation of surplus soluble proteins. However, it is still an enigma if CMA is a bonus or curse for PD. Case-control studies and cellular and animal models have deciphered the contribution of impaired CMA in PD. Current article updates the role of CMA in toxicant models and recapitulates the evidences that have highlighted a link between impaired CMA and PD. Although PD is an irreversible happening and CMA is a dual edging phenomenon, it is anticipated that fine-tuning of the latter encounters the former to a certain extent. Besides, the truth, embellishment, and propaganda regarding the issue are also emphasized in the final segment of the article.
KeywordsParkinson’s disease Chaperone-mediated autophagy Toxicant models Parkinsonism
Manish Kumar Tripathi, Charul Rajput, Saumya Mishra, and Mohd Sami ur Rasheed are grateful to the Department of Biotechnology, Government of India (GoI), Council of Scientific and Industrial Research (GoI), University Grants Commission (GoI), and Department of Science and Technology (GoI), respectively. The CSIR-IITR communication number of this article is 3532.
Science and Engineering Research Board (SERB) (GoI) is acknowledged for providing the financial support (Project Reference No.: EMR/2016/005041) to Mahendra Pratap Singh.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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