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The Journal of Neuroscience, July 15, 2009, 29(28):9104-9114; doi:10.1523/JNEUROSCI.2250-09.2009

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Neurobiology of Disease
Loss of Hsp70 Exacerbates Pathogenesis But Not Levels of Fibrillar Aggregates in a Mouse Model of Huntington's Disease

Jennifer L. Wacker,¹ Shao-Yi Huang,² Andrew D. Steele,⁶ Rebecca Aron,² Gregor P. Lotz,² QuangVu Nguyen,¹ Flaviano Giorgini,¹ Erik D. Roberson,² Susan Lindquist,⁶ Eliezer Masliah,⁷ and Paul J. Muchowski^1,2,3,4,5

¹Department of Pharmacology, University of Washington, Seattle, Washington 98195, ²Gladstone Institute of Neurological Disease, ³The Taube-Koret Center for Huntington's Disease Research, and ⁴Departments of Biochemistry and Biophysics and ⁵Neurology, University of California, San Francisco, San Francisco, California 94158, ⁶Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, and ⁷Department of Neurosciences, University of California, San Diego, La Jolla, California 92093

Correspondence should be addressed to Paul J. Muchowski, Gladstone Institute of Neurological Disease, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158. Email: pmuchowski{at}gladstone.ucsf.edu

Endogenous protein quality control machinery has long been suspected of influencing the onset and progression of neurodegenerative diseases characterized by accumulation of misfolded proteins. Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of a polyglutamine (polyQ) tract in the protein huntingtin (htt), which leads to its aggregation and accumulation in inclusion bodies. Here, we demonstrate in a mouse model of HD that deletion of the molecular chaperones Hsp70.1 and Hsp70.3 significantly exacerbated numerous physical, behavioral and neuropathological outcome measures, including survival, body weight, tremor, limb clasping and open field activities. Deletion of Hsp70.1 and Hsp70.3 significantly increased the size of inclusion bodies formed by mutant htt exon 1, but surprisingly did not affect the levels of fibrillar aggregates. Moreover, the lack of Hsp70s significantly decreased levels of the calcium regulated protein c-Fos, a marker for neuronal activity. In contrast, deletion of Hsp70s did not accelerate disease in a mouse model of infectious prion-mediated neurodegeneration, ruling out the possibility that the Hsp70.1/70.3 mice are nonspecifically sensitized to all protein misfolding disorders. Thus, endogenous Hsp70s are a critical component of the cellular defense against the toxic effects of misfolded htt protein in neurons, but buffer toxicity by mechanisms independent of the deposition of fibrillar aggregates.

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Received May 13, 2009; accepted June 11, 2009.

Correspondence should be addressed to Paul J. Muchowski, Gladstone Institute of Neurological Disease, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158. Email: pmuchowski{at}gladstone.ucsf.edu

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