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New Directions for Neurodegenerative Disease Therapy: Using Chemical Compounds to Boost the Formation of Mutant Protein Inclusions

Volume 5, Issue 14   July 15, 2006
Pages 1477 - 1480
http://dx.doi.org/10.4161/cc.5.14.2929
Authors: Ruth A. Bodner, David E. Housman and Aleksey G. Kazantsev

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Abstract:
Neurodegenerative disease such as Huntington’s, Parkinson’s, and Alzheimer’s diseases are marked by neuronal accumulation of toxic misfolded protein. Developing therapies for these misfolding diseases requires finding chemical compounds that can either clear toxic misfolded protein, or can protect neurons from their impact. Such compounds could not only provide the starting points for potential drugs, but could also provide valuable research tools for untangling the complexities of the disease process. Until now, chemical screens for these diseases have focused on finding compounds that prevent aggregation of mutant protein. We recently published a compound, B2, which promotes the formation of large inclusions by mutant Huntingtin and α-synuclein, while rescuing some of the toxic effects of these proteins. As inclusions were long believed to be toxic to cells, this contradicts previous therapeutic approaches. At the same time, the results support growing evidence for the protective effects of inclusions. In this review, we discuss these results, and place them in the context of ongoing therapeutic discovery efforts for HD and other neurodegenerative diseases.

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