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Strategies for Conferring Neuroprotection and Countering the High Threshold for Induction of the Stress Response in Motor Neurons

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Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

Part of the book series: Heat Shock Proteins ((HESP,volume 3))

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Abstract

The higher threshold for stress-induced upregulation of heat shock genes in certain populations of neurons, including motor neurons, has implications for their preferential vulnerability to disease and poses challenges for therapeutic intervention. One approach for identifying compounds that are effective in motor neurons involves understanding the mechanisms of heat shock gene regulation and hypothesis-driven therapeutic design. Central to stress-induced activation of heat shock genes is the transcription factor Hsf1, which must be released from Hsp90 complexes, translocate to the nucleus, bind to heat shock elements, and become activated. Most known inducers and co-inducers of the heat shock response promote one or more of these steps, but not all compounds are effective in motor neurons. However, other elements in the promoters of heat shock genes and heat shock transcription factors also contribute to constitutive and stress-induced regulation of heat shock genes and are potential therapeutic targets. Another approach is to screen chemical libraries using a test system that expresses motor neuronal properties, with positive hits being validated in vivo. The most effective therapies will be those that upregulate multiple chaperones and co-chaperones that enable refolding and degradation in addition to sequestering misfolded proteins

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Authors and Affiliations

  1. Department of Neurology/Neurosurgery and Montreal, Neurological Institute, McGill University, Montreal, QC, Canada

    Heather D. Durham

  2. Neurotoxicology Research Laboratory, Montreal Neurological Institute, 3801 University Street, Room 649, Montreal, QC, Canada H3A 2B4

    Heather D. Durham

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  1. Heather D. Durham
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Editors and Affiliations

  1. Effie and Wofford Cain Centennial Endowed Chair in Clinical Pathology, Chief, Division of Investigative Pathology, Scott & White Memorial Hospital and Clinic and The Texas A&M Health Science Center College of Medicine, Temple, Texas, U.S.A

    Alexzander A.A. Asea

  2. Department of Biological Sciences, Center for the Neurobiology of Stress, University of Toronto at Scarborough, Toronto, ON, Canada

    Ian R. Brown

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Durham, H.D. (2008). Strategies for Conferring Neuroprotection and Countering the High Threshold for Induction of the Stress Response in Motor Neurons. In: Asea, A.A., Brown, I.R. (eds) Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection. Heat Shock Proteins, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-8231-3_10

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