Human Molecular Genetics, 2001, Vol. 10, No. 14 1511-1518
© 2001 Oxford University Press
Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice
1Department of Pediatrics, 2Department of Neurology, 3Department of Pathology, 4Department of Molecular and Human Genetics, 5Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA, 6Department of Physiology, Loyola University, Maywood, IL 60153, USA, 7Departments of Laboratory Medicine and Pathology and Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, USA and 8Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, San Diego, CA 92103, USA
Many neurodegenerative diseases are caused by gain-of-function mechanisms in which the disease-causing protein is altered, becomes toxic to the cell, and aggregates. Among these ‘proteinopathies’ are Alzheimer’s and Parkinson’s disease, prion disorders and polyglutamine diseases. Members of this latter group, also known as triplet repeat diseases, are caused by the expansion of unstable CAG repeats coding for glutamine within the respective proteins. Spinocerebellar ataxia type 1 (SCA1) is one such disease, characterized by loss of motor coordination due to the degeneration of cerebellar Purkinje cells and brain stem neurons. In SCA1 and several other polyglutamine diseases, the expanded protein aggregates into nuclear inclusions (NIs). Because these NIs accumulate molecular chaperones, ubiquitin and proteasomal subunits—all components of the cellular protein re-folding and degradation machinery—we hypothesized that protein misfolding and impaired protein clearance might underlie the pathogenesis of polyglutamine diseases. Over-expressing specific chaperones reduces protein aggregation in transfected cells and suppresses neurodegeneration in invertebrate animal models of polyglutamine disorders. To determine whether enhancing chaperone activity could mitigate the phenotype in a mammalian model, we crossbred SCA1 mice with mice over-expressing a molecular chaperone (inducible HSP70 or iHSP70). We found that high levels of HSP70 did indeed afford protection against neurodegeneration.
+ To whom correspondence should be addressed at: Department of Pediatrics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Tel: +1 713 798 6558; Fax: +1 713 798 8728; Email: hzoghbi@bcm.tmc.eduPresent address: Christopher J. Cummings, AGY Therapeutics, 290 Utah Avenue, South San Francisco, CA 94080, USA
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