Human Molecular Genetics Advance Access published online on September 2, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg305
© 2003 by Oxford University Press
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1 Institute of Neurosciences, Swiss Federal Institute of Technology Lausanne, EPFL, Switzerland
* To whom correspondence should be addressed. E-mail: nicole.deglon{at}epfl.ch.
The ability to overexpress full-length huntingtin or large fragments represents an important challenge to mimic Huntington's pathology and reproduce all stages of the disease in a time frame compatible with rodent life span. In the present study, tetracycline-regulated lentiviral vectors leading to high expression levels were used to accelerate the pathological process. Rats were simultaneously injected with vectors coding for the transactivator and WT or mutated huntingtin (TRE-853-19Q/82Q) in the left and right striatum respectively, and analyzed in the "on" and "off" conditions. Overexpression of TRE-853-19Q protein or residual expression of TRE-853-82Q in "off" condition did not cause any significant neuronal pathology. Overexpressed TRE-853-82Q protein led to proteolytic release of N-terminal htt fragments, nuclear aggregation, and a striatal dysfunction as revealed by decrease of DARPP-32 staining but absence of NeuN down-regulation. The differential effect on the DARPP-32/NeuN neuronal staining was observed as early as one month after injection and maintained at three months. In contrast, expression of a shorter htt form (htt171-82Q) did not require processing prior formation of nuclear aggregates and caused decrease of both DARPP-32 and NeuN neuronal markers at one month post-injection suggesting that polyQ pathology may be dependent on protein context. Finally, the reversibility of the pathology was assessed. Huntingtin expression was turn "on" for one month and then shut "off" for two months. A recovery of DARPP-32 immunoreactivity and a clearance of huntingtin aggregates were observed in animals treated with doxycycline. These results suggest that tetracycline-regulated system may be particularly attractive to model HD and induce early and reversible striatal neuropathology in vivo.
Article
EARLY AND REVERSIBLE NEUROPATHOLOGY INDUCED BY TETRACYCLINE-REGULATED LENTIVIRAL OVER-EXPRESSION OF MUTANT HUNTINGTIN IN RAT STRIATUM
2 Institut de Génétique et Biologie Cellulaire et Moléculaire, CNRS/INSERM/ULP, Illkirch, France
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