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Unformatted text preview: Research article The Journal of Clinical Investigation http://www.jci.org Volume117 Number10 October2007 2889 Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease Sung-Rae Cho, 1 Abdellatif Benraiss, 1,2 Eva Chmielnicki, 2 Amer Samdani, 2,3 Aris Economides, 4 and Steven A. Goldman 1,2 1 Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA. 2 Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York, USA. 3 Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland, USA. 4 Regeneron Pharmaceuticals, Tarrytown, New York, USA. Ependymal overexpression of brain-derived neurotrophic factor (BDNF) stimulates neuronal addition to the adult striatum, from subependymal progenitor cells. Noggin, by suppressing subependymal gliogenesis and increasing progenitor availability, potentiates this process. We asked whether BDNF/Noggin overexpression might be used to recruit new striatal neurons in R6/2 huntingtin transgenic mice. R6/2 mice injected with adenoviral BDNF and adenoviral Noggin (AdBDNF/AdNoggin) recruited BrdU + III-tubulin + neurons, which developed as DARPP-32 + and GABAergic medium spiny neurons that expressed either enkephalin or sub- stance P and extended fibers to the globus pallidus. Only AdBDNF/AdNoggin-treated R6/2 mice harbored migrating doublecortin-defined neuroblasts in their striata, and the new neurons expressed p27 as a marker of mitotic quiescence after parenchymal integration. AdBDNF/AdNoggin-treated R6/2 mice sustained their rotarod performance and open-field activity and survived longer than did AdNull-treated and untreated con- trols. Neither motor performance nor survival improved in R6/2 mice treated only with AdBDNF, and intra- ventricular infusion of the mitotic inhibitor Ara-C completely blocked the performance and survival effects of AdBDNF/AdNoggin, suggesting that the benefits of AdBDNF/AdNoggin derived from neuronal addition. Thus, BDNF and Noggin induced striatal neuronal regeneration, delayed motor impairment, and extended survival in R6/2 mice, suggesting a new therapeutic strategy in Huntington disease. Introduction Neuralstemcellspersistthroughouttheventricularsubependyma oftheadultvertebratebrain(15).Theseadultneuralstemcells canbeinducedtodifferentiateandsurviveasneuronsunderthe influenceofbrain-derivedneurotrophicfactor(BDNF)(69).When administeredintraventricularly,BDNFincreasesneuronaladdition totheolfactorybulb,atypicalneurogenicsite(10).Inaddition, BDNFadministrationandoverexpressionarebothassociatedwith heterotopicneuronaladditiontotheneostriatum,aregionofthe brainthatistypicallynon-neurogenicinadults(1113).Thesebrainthatistypicallynon-neurogenicinadults(1113)....
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This note was uploaded on 09/29/2010 for the course BIOLOGY BISP 194 taught by Professor Hermann during the Fall '10 term at UCSD.
- Fall '10