Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease.
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.
Cho
Sung-Rae
SR
Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.
Benraiss
Abdellatif
A
Chmielnicki
Eva
E
Samdani
Amer
A
Economides
Aris
A
Goldman
Steven A
SA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004745:Enkephalins / Q000032:analysis / Q000378:metabolism; D005917:Globus Pallidus / Q000166:cytology / Q000502:physiology; D006816:Huntington Disease / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D017072:Neostriatum / Q000166:cytology / Q000502:physiology*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D012038:Regeneration; D013373:Substance P / Q000032:analysis / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D000099176:Noggin Protein
D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; D004745:Enkephalins; D013373:Substance P; D014404:Tubulin; D000099176:Noggin Protein