Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis
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 wit...
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MDPI AG
2023-05-01
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| author | Sumit Kinger Ankur Rakesh Dubey Prashant Kumar Yuvraj Anandrao Jagtap Akash Choudhary Amit Kumar Vijay Kumar Prajapati Rohan Dhiman Amit Mishra |
| author_facet | Sumit Kinger Ankur Rakesh Dubey Prashant Kumar Yuvraj Anandrao Jagtap Akash Choudhary Amit Kumar Vijay Kumar Prajapati Rohan Dhiman Amit Mishra |
| author_sort | Sumit Kinger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T04:22:15Z |
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| id | doaj.art-6983c1ce8a3b4182aaf2a8e8b00e078e |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T04:22:15Z |
| publishDate | 2023-05-01 |
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| series | Cells |
| spelling | doaj.art-6983c1ce8a3b4182aaf2a8e8b00e078e2023-11-17T22:44:04ZengMDPI AGCells2073-44092023-05-01129130210.3390/cells12091302Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral SclerosisSumit Kinger0Ankur Rakesh Dubey1Prashant Kumar2Yuvraj Anandrao Jagtap3Akash Choudhary4Amit Kumar5Vijay Kumar Prajapati6Rohan Dhiman7Amit Mishra8Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur 342037, IndiaCellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur 342037, IndiaCellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur 342037, IndiaCellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur 342037, IndiaCellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur 342037, IndiaDiscipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, IndiaDepartment of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer 305817, IndiaLaboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, IndiaCellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur 342037, IndiaAmyotrophic 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.https://www.mdpi.com/2073-4409/12/9/1302ALSchaperonesHSP70HSP27HSPB8HSP40 |
| spellingShingle | Sumit Kinger Ankur Rakesh Dubey Prashant Kumar Yuvraj Anandrao Jagtap Akash Choudhary Amit Kumar Vijay Kumar Prajapati Rohan Dhiman Amit Mishra Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis Cells ALS chaperones HSP70 HSP27 HSPB8 HSP40 |
| title | Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis |
| title_full | Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis |
| title_fullStr | Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis |
| title_full_unstemmed | Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis |
| title_short | Molecular Chaperones’ Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis |
| title_sort | molecular chaperones potential against defective proteostasis of amyotrophic lateral sclerosis |
| topic | ALS chaperones HSP70 HSP27 HSPB8 HSP40 |
| url | https://www.mdpi.com/2073-4409/12/9/1302 |
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