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Lanosterol Suppresses the Aggregation and Cytotoxicity of Misfolded Proteins Linked with Neurodegenerative Diseases

Upadhyay, Arun, Amanullah, Ayeman, Mishra, Ribhav, Kumar, Amit, Mishra, Amit·2018·Molecular Neurobiology
DOI 10.1007/s12035-016-0377-2
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Abstract

Accumulation of misfolded or aberrant proteins in neuronal cells is linked with neurodegeneration and other pathologies. Which molecular mechanisms fail and cause inappropriate folding of proteins and what is their relationship to cellular toxicity is not well known. How does it happen and what are the probable therapeutic or molecular approaches to counter them are also not clear. Here, we demonstrate that treatment of lanosterol diminishes aberrant proteotoxic aggregation and mitigates their cytotoxicity via induced expression of co-chaperone CHIP and elevated autophagy. The addition of lanosterol not only reduces aggregation of mutant bonafide misfolded proteins but also effectively prevents accumulation of various mutant disease-prone proteotoxic proteins. Finally, we observed that lanosterol mitigates cytotoxicity in cells, mediated by different stress-inducing agents. Taken together, our present results suggest that upregulation of cellular molecular chaperones, primarily using small molecules, can probably offer an efficient therapeutic approach in the future against misfolding of different disease-causing proteins and neurodegenerative disorders. Graphical Abstract ᅟ.

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  • The treatment decreased the number and size of muHTT aggregates and improved motor deficits in R6/2 mice and provided long-lasting improvement in zQ175 HD mice.

    “The treatment decreased the number and size of muHTT aggregates and improved motor deficits in R6/2 mice 54 and provided long-lasting improvement in zQ175 HD mice 56 .”

    From SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes (2021) · cites this paper as [56]

  • In a similar gene therapy approach, the gene encoding for CYP46A1 was delivered into striatal neurons of HD mice by use of an AAVrh10 vector.

    “In a similar gene therapy approach, the gene encoding for CYP46A1, the enzyme that converts cholesterol into the neuronal cholesterol catabolite 24S-OHC, was delivered into striatal neurons of HD mice by use of an AAVrh10 vector 55,56 .”

    From SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes (2021) · cites this paper as [56]

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Metadata

Authors
Upadhyay, A., Amanullah, A., Mishra, R., Kumar, A., & Mishra, A.
Venue
Molecular Neurobiology
Publisher
Springer Science and Business Media LLC
Published
2017-01-19
Volume
55
Issue
2
Pages
1169-1182
ISSN
  • 0893-7648
  • 1559-1182
DOI
10.1007/s12035-016-0377-2
Cited by
39
References
1
Language
en
Licence
www.springer.com/tdm (unspecified)
Funders
  • Ramalinganswami Fellowship (BT/RLF/Reentry/11/2010)
  • Extra Mural Research Funding (Individual Centric): Science and Engineering Research Board (SERB) (EMR/2016/000716)

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