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Review

Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis

by
Sumit Kinger
1,†,
Ankur Rakesh Dubey
1,†,
Prashant Kumar
1,
Yuvraj Anandrao Jagtap
1,
Akash Choudhary
1,
Amit Kumar
2,
Vijay Kumar Prajapati
3,
Rohan Dhiman
4 and
Amit Mishra
1,*
1
Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur 342037, India
2
Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, India
3
Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer 305817, India
4
Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, India
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2023, 12(9), 1302; https://doi.org/10.3390/cells12091302
Submission received: 11 January 2023 / Revised: 24 April 2023 / Accepted: 27 April 2023 / Published: 2 May 2023
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Understanding the Pathogenetic Mechanisms for the Development of New Therapies)
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Abstract

Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of polypeptides is mediated by molecular chaperones, preventing their pathogenic aggregation. The mutant protein expression in ALS is linked with the entrapment and depletion of chaperone capacity. The lack of a thorough understanding of chaperones’ involvement in ALS pathogenesis presents a significant challenge in its treatment. Here, we review how the accumulation of the ALS-linked mutant FUS, TDP-43, SOD1, and C9orf72 proteins damage cellular homeostasis mechanisms leading to neuronal loss. Further, we discuss how the HSP70 and DNAJ family co-chaperones can act as potential targets for reducing misfolded protein accumulation in ALS. Moreover, small HSPB1 and HSPB8 chaperones can facilitate neuroprotection and prevent stress-associated misfolded protein apoptosis. Designing therapeutic strategies by pharmacologically enhancing cellular chaperone capacity to reduce mutant protein proteotoxic effects on ALS pathomechanisms can be a considerable advancement. Chaperones, apart from directly interacting with misfolded proteins for protein quality control, can also filter their toxicity by initiating strong stress-response pathways, modulating transcriptional expression profiles, and promoting anti-apoptotic functions. Overall, these properties of chaperones make them an attractive target for gaining fundamental insights into misfolded protein disorders and designing more effective therapies against ALS.
Keywords: ALS; chaperones; HSP70; HSP27; HSPB8; HSP40 ALS; chaperones; HSP70; HSP27; HSPB8; HSP40

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MDPI and ACS Style

Kinger, S.; Dubey, A.R.; Kumar, P.; Jagtap, Y.A.; Choudhary, A.; Kumar, A.; Prajapati, V.K.; Dhiman, R.; Mishra, A. Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis. Cells 2023, 12, 1302. https://doi.org/10.3390/cells12091302

AMA Style

Kinger S, Dubey AR, Kumar P, Jagtap YA, Choudhary A, Kumar A, Prajapati VK, Dhiman R, Mishra A. Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis. Cells. 2023; 12(9):1302. https://doi.org/10.3390/cells12091302

Chicago/Turabian Style

Kinger, Sumit, Ankur Rakesh Dubey, Prashant Kumar, Yuvraj Anandrao Jagtap, Akash Choudhary, Amit Kumar, Vijay Kumar Prajapati, Rohan Dhiman, and Amit Mishra. 2023. "Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis" Cells 12, no. 9: 1302. https://doi.org/10.3390/cells12091302

APA Style

Kinger, S., Dubey, A. R., Kumar, P., Jagtap, Y. A., Choudhary, A., Kumar, A., Prajapati, V. K., Dhiman, R., & Mishra, A. (2023). Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis. Cells, 12(9), 1302. https://doi.org/10.3390/cells12091302

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