03-06-08(2:52:39)
Authors:
Franich NR 1, Fitzsimons HL 2, Klugmann M 3, During MJ 1,4, and Young D 1,5
Institutions:
1. Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
2. Neurologix Inc., Fort Lee, New Jersey, USA
3. Department of Physiological Chemistry, Johannes Gutenberg University, Mainz, Germany
4. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
5. Department of Pharmacology & Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
Title of abstract : AAV vector-mediated heat shock protein expression modulates mutant huntingtin aggregation and toxicity in a genetic rat model of Huntington’s disease
Abstract text:
Aberrant protein accumulation is a common feature of neurodegenerative disorders including polyglutamine expansion (polyQ) diseases. Numerous studies have shown that over-expression of heat shock protein HSP70 and its co-chaperones in cell culture and in vivo models of polyQ diseases results in amelioration of pathological hallmarks of these diseases, including protein aggregation and/or toxicity. Furthermore, upregulation of molecular chaperone expression, either pharmacologically or using recombinant constitutively active heat shock transcription factor 1 (HSF1) has resulted in suppression of aggregation and/or toxicity in various models of neurodegenerative disorders. However, results in transgenic mouse models of Huntington’s disease (HD) have been disappointing, with little or no therapeutic benefit reported. As a complementary approach to preclinical screening of chaperone over-expression in transgenic models of HD, we have used adeno-associated virus (AAV) vector-mediated gene transfer to investigate the effect of increased chaperone expression on inclusion formation and striatal neuronal toxicity in a genetic rat model of HD. We directly compared the effects of over-expression of HSP70, HSP40, and H-BH, a constitutively active form of HSF1, which facilitates upregulation of various molecular chaperones (including HSP40 and HSP70). While H-BH or HSP40 partially inhibited inclusion formation, HSP70 over-expression resulted in a moderate level of neuroprotection.
