Lanosterol elevates cytoprotective response through induced-proteasomal degradation of aberrant proteins.

Sumit Kinger, Yuvraj Anandrao Jagtap, Ankur Rakesh Dubey, Prashant Kumar, Akash Choudhary, Rohan Dhiman, Vijay Kumar Prajapati, Deepak Chitkara, Krishna Mohan Poluri, Amit Mishra

Biochimica et biophysica acta. Molecular cell research 2024 Feb

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Efficient protein synthesis is a basic requirement of our cells to replace the old or defective proteins from the intrinsic crowded biomolecular environment. The interconnection among synthesis, folding, and degradation of proteins represents central paradigm to proteostasis. Failure of protein quality control (PQC) mechanisms results in the disturbance and inadequate functions of proteome. The consequent misfolded protein accumulation can form the basis of neurodegeneration onset and largely represents imperfect aging. Understanding how cells improve the function of deregulated PQC mechanisms to establish and maintain proteostasis against the unwanted sequestration of normal proteins with misfolded proteinaceous inclusions is a major challenge. Here we show that treatment of Lanosterol, a cholesterol synthesis pathway intermediate, induces Proteasome proteolytic activities and, therefore, supports the PQC mechanism for the elimination of intracellular aberrant proteins. The exposure of Lanosterol not only promotes Proteasome catalytic functions but also elevates the removal of both bona fide and neurodegenerative diseases associated toxic proteins. Our current study suggests that increasing Proteasome functions with the help of small molecules such as Lanosterol could serve as a cytoprotective therapeutic approach against abnormal protein accumulation. Cumulatively, based on findings in this study, we can understand the critical importance of small molecules and their potential therapeutic influence in re-establishing disturbed proteostasis linked with neurodegeneration. Copyright © 2023 Elsevier B.V. All rights reserved.

Citation

Sumit Kinger, Yuvraj Anandrao Jagtap, Ankur Rakesh Dubey, Prashant Kumar, Akash Choudhary, Rohan Dhiman, Vijay Kumar Prajapati, Deepak Chitkara, Krishna Mohan Poluri, Amit Mishra. Lanosterol elevates cytoprotective response through induced-proteasomal degradation of aberrant proteins. Biochimica et biophysica acta. Molecular cell research. 2024 Feb;1871(2):119631