Early and reversible neuropathology induced by tetracycline-regulated lentiviral overexpression of mutant huntingtin in rat striatum.

Details

Serval ID
serval:BIB_F4E0153B1145
Type
Article: article from journal or magazin.
Collection
Publications
Title
Early and reversible neuropathology induced by tetracycline-regulated lentiviral overexpression of mutant huntingtin in rat striatum.
Journal
Human Molecular Genetics
Author(s)
Régulier E., Trottier Y., Perrin V., Aebischer P., Déglon N.
ISSN
0964-6906 (Print)
ISSN-L
0964-6906
Publication state
Published
Issued date
2003
Volume
12
Number
21
Pages
2827-2836
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
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 wild type (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 1 month after injection and maintained at 3 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 1 month and then shut 'off' for 2 months. Recovery of DARPP-32 immunoreactivity and clearance of huntingtin aggregates were observed in animals treated with doxycycline. These results suggest that a tetracycline-regulated system may be particularly attractive to model Huntington's disease and induce early and reversible striatal neuropathology in vivo.
Keywords
Animals, Cell Nucleus/metabolism, Corpus Striatum/metabolism, Corpus Striatum/pathology, Dopamine and cAMP-Regulated Phosphoprotein 32, Doxycycline/chemistry, Female, Gene Expression Regulation, Genetic Vectors, Humans, Huntington Disease/genetics, Huntington Disease/metabolism, Lentivirus/genetics, Mutation, Nerve Tissue Proteins/genetics, Nerve Tissue Proteins/metabolism, Nuclear Proteins/genetics, Nuclear Proteins/metabolism, Phosphoproteins/metabolism, Rats, Rats, Wistar, Tetracycline/chemistry
Pubmed
Web of science
Create date
13/12/2011 16:33
Last modification date
20/08/2019 16:21
Usage data