PMID- 17885687 OWN - NLM STAT- MEDLINE DCOM- 20071127 LR - 20220408 IS - 0021-9738 (Print) IS - 0021-9738 (Linking) VI - 117 IP - 10 DP - 2007 Oct TI - Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. PG - 2889-902 AB - 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(+)betaIII-tubulin(+) neurons, which developed as DARPP-32(+) and GABAergic medium spiny neurons that expressed either enkephalin or substance 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 controls. Neither motor performance nor survival improved in R6/2 mice treated only with AdBDNF, and intraventricular 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. FAU - Cho, Sung-Rae AU - Cho SR AD - Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA. FAU - Benraiss, Abdellatif AU - Benraiss A FAU - Chmielnicki, Eva AU - Chmielnicki E FAU - Samdani, Amer AU - Samdani A FAU - Economides, Aris AU - Economides A FAU - Goldman, Steven A AU - Goldman SA LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Clin Invest JT - The Journal of clinical investigation JID - 7802877 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Carrier Proteins) RN - 0 (Enkephalins) RN - 0 (Tubulin) RN - 148294-77-3 (noggin protein) RN - 33507-63-0 (Substance P) SB - IM MH - Adenoviridae/genetics MH - Animals MH - Brain-Derived Neurotrophic Factor/*genetics MH - Carrier Proteins/*genetics MH - Disease Models, Animal MH - Disease Progression MH - Enkephalins/analysis/metabolism MH - Globus Pallidus/cytology/physiology MH - Huntington Disease/physiopathology/*therapy MH - Mice MH - Mice, Transgenic MH - Mitosis MH - Neostriatum/cytology/*physiology MH - Neurons/chemistry/metabolism/*physiology MH - *Regeneration MH - Substance P/analysis/metabolism MH - Tubulin/metabolism PMC - PMC1978427 EDAT- 2007/09/22 09:00 MHDA- 2007/12/06 09:00 PMCR- 2007/10/01 CRDT- 2007/09/22 09:00 PHST- 2007/02/12 00:00 [received] PHST- 2007/07/06 00:00 [accepted] PHST- 2007/09/22 09:00 [pubmed] PHST- 2007/12/06 09:00 [medline] PHST- 2007/09/22 09:00 [entrez] PHST- 2007/10/01 00:00 [pmc-release] AID - 31778 [pii] AID - 10.1172/JCI31778 [doi] PST - ppublish SO - J Clin Invest. 2007 Oct;117(10):2889-902. doi: 10.1172/JCI31778.