000160850 001__ 160850
000160850 005__ 20180913060249.0
000160850 0247_ $$2doi$$a10.1093/hmg/ddn106
000160850 02470 $$2ISI$$a000257181300001
000160850 037__ $$aARTICLE
000160850 245__ $$aStriatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease
000160850 269__ $$a2008
000160850 260__ $$c2008
000160850 336__ $$aJournal Articles
000160850 520__ $$aMachado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study, we aimed at overexpressing ataxin-3 in the rat brain using lentiviral vectors (LV), to generate an in vivo MJD genetic model and, to study the disorder in defined brain regions: substantia nigra, an area affected in MJD, cortex and striatum, regions not previously reported to be affected in MJD. LV encoding mutant or wild-type human ataxin-3 was injected in the brain of adult rats and the animals were tested for behavioral deficits and neuropathological abnormalities. Striatal pathology was confirmed in transgenic mice and human tissue. In substantia nigra, unilateral overexpression of mutant ataxin-3 led to: apomorphine-induced turning behavior; formation of ubiquitinated ataxin-3 aggregates; alpha-synuclein immunoreactivity; and loss of dopaminergic markers (TH and VMAT2). No neuropathological changes were observed upon wild-type ataxin-3 overexpression. Mutant ataxin-3 expression in striatum and cortex, resulted in accumulation of misfolded ataxin-3, and within striatum, loss of neuronal markers. Striatal pathology was confirmed by observation in MJD transgenic mice of ataxin-3 aggregates and substantial reduction of DARPP-32 immunoreactivity and, in human striata, by ataxin-3 inclusions, immunoreactive for ubiquitin and alpha-synuclein. This study demonstrates the use of LV encoding mutant ataxin-3 to produce a model of MJD and brings evidence of striatal pathology, suggesting that this region may contribute to dystonia and chorea observed in some MJD patients and may represent a target for therapies.
000160850 6531_ $$aSpinocerebellar Ataxia Type-3
000160850 6531_ $$aPositron-Emission-Tomography
000160850 6531_ $$aExpanded Polyglutamine
000160850 6531_ $$aIntranuclear Inclusions
000160850 6531_ $$aNeuronal Degeneration
000160850 6531_ $$aNuclear-Localization
000160850 6531_ $$aHuntingtons-Disease
000160850 6531_ $$aMarinesco Bodies
000160850 6531_ $$aTransgenic Mice
000160850 6531_ $$aAlpha-Synuclein
000160850 700__ $$aAlves, Sandro
000160850 700__ $$aRegulier, Etienne
000160850 700__ $$aNascimento-Ferreira, Isabel
000160850 700__ $$aHassig, Raymonde
000160850 700__ $$aDufour, Noelle
000160850 700__ $$aKoeppen, Arnulf
000160850 700__ $$aCarvalho, Ana Luisa
000160850 700__ $$aSimoes, Sergio
000160850 700__ $$aPedroso de Lima, Maria C.
000160850 700__ $$aBrouillet, Emmanuel
000160850 700__ $$aGould, Veronica Colomer
000160850 700__ $$aDeglon, Nicole
000160850 700__ $$ade Almeida, Luis Pereira
000160850 773__ $$j17$$q2071-2083$$tHuman Molecular Genetics
000160850 909C0 $$0252372$$pSV$$xU10445
000160850 909CO $$ooai:infoscience.tind.io:160850$$pSV$$particle
000160850 917Z8 $$xWOS-2010-11-30
000160850 937__ $$aEPFL-ARTICLE-160850
000160850 973__ $$aEPFL$$rREVIEWED$$sPUBLISHED
000160850 980__ $$aARTICLE