Pharmacological promotion of inclusion formation: A therapeutic approach for Huntington's and Parkinson's diseases

Ruth A. Bodner; Tiago Fleming Outeiro; Stephen Altmann; Michele M. Maxwell; Stephanie H. Cho; Bradley T. Hyman; Pamela J. McLean; Anne B. Young; David E. Housman; Aleksey G. Kazantsev

doi:10.1073/pnas.0511256103

Pharmacological promotion of inclusion formation: A therapeutic approach for Huntington's and Parkinson's diseases

Ruth A. Bodner, Tiago Fleming Outeiro, Stephen Altmann, Michele M. Maxwell, Stephanie H. Cho, Bradley T. Hyman, Pamela J. McLean, Anne B. Young, David E. Housman, Aleksey G. Kazantsev

Neuroscience

Research output: Contribution to journal › Article › peer-review

219 Scopus citations

Abstract

Misfolded proteins accumulate in many neurodegenerative diseases, including huntingtin in Huntington's disease and α-synuclein in Parkinson's disease. The disease-causing proteins can take various conformations and are prone to aggregate and form larger cytoplasmic or nuclear inclusions. One approach to the development of therapeutic intervention for these diseases has been to identify chemical compounds that reduce the size or number of inclusions. We have, however, identified a compound that promotes inclusion formation in cellular models of both Huntington's disease and Parkinson's disease. Of particular interest, this compound prevents huntingtin-mediated proteasome dysfunction and reduces α-synuclein-mediated toxicity. These results demonstrate that compounds that increase inclusion formation may actually lessen cellular pathology in both Huntington's and Parkinson's diseases, suggesting a therapeutic approach for neurodegenerative diseases caused by protein misfolding.

Original language	English (US)
Pages (from-to)	4246-4251
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	103
Issue number	11
DOIs	https://doi.org/10.1073/pnas.0511256103
State	Published - Mar 14 2006

Keywords

Misfolded proteins
Neurodegenerative disease

ASJC Scopus subject areas

General

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10.1073/pnas.0511256103

Cite this

Bodner, R. A., Outeiro, T. F., Altmann, S., Maxwell, M. M., Cho, S. H., Hyman, B. T., McLean, P. J., Young, A. B., Housman, D. E., & Kazantsev, A. G. (2006). Pharmacological promotion of inclusion formation: A therapeutic approach for Huntington's and Parkinson's diseases. Proceedings of the National Academy of Sciences of the United States of America, 103(11), 4246-4251. https://doi.org/10.1073/pnas.0511256103

Pharmacological promotion of inclusion formation: A therapeutic approach for Huntington's and Parkinson's diseases. / Bodner, Ruth A.; Outeiro, Tiago Fleming; Altmann, Stephen et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 11, 14.03.2006, p. 4246-4251.

Research output: Contribution to journal › Article › peer-review

Bodner, RA, Outeiro, TF, Altmann, S, Maxwell, MM, Cho, SH, Hyman, BT, McLean, PJ, Young, AB, Housman, DE & Kazantsev, AG 2006, 'Pharmacological promotion of inclusion formation: A therapeutic approach for Huntington's and Parkinson's diseases', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 11, pp. 4246-4251. https://doi.org/10.1073/pnas.0511256103

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abstract = "Misfolded proteins accumulate in many neurodegenerative diseases, including huntingtin in Huntington's disease and α-synuclein in Parkinson's disease. The disease-causing proteins can take various conformations and are prone to aggregate and form larger cytoplasmic or nuclear inclusions. One approach to the development of therapeutic intervention for these diseases has been to identify chemical compounds that reduce the size or number of inclusions. We have, however, identified a compound that promotes inclusion formation in cellular models of both Huntington's disease and Parkinson's disease. Of particular interest, this compound prevents huntingtin-mediated proteasome dysfunction and reduces α-synuclein-mediated toxicity. These results demonstrate that compounds that increase inclusion formation may actually lessen cellular pathology in both Huntington's and Parkinson's diseases, suggesting a therapeutic approach for neurodegenerative diseases caused by protein misfolding.",

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AU - Cho, Stephanie H.

AU - Hyman, Bradley T.

AU - McLean, Pamela J.

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Pharmacological promotion of inclusion formation: A therapeutic approach for Huntington's and Parkinson's diseases

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