Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease

Sung-Rae Cho, Abdellatif Benraiss, Eva Chmielnicki, Amer Samdani, Aris Economides, Steven A. Goldman

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Abstract

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+7beta;III-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.

Original languageEnglish
Pages (from-to)2889-2902
Number of pages14
JournalJournal of Clinical Investigation
Volume117
Issue number10
DOIs
Publication statusPublished - 2007 Oct 1

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Huntington Disease
Brain-Derived Neurotrophic Factor
Neurogenesis
Disease Progression
Neurons
Corpus Striatum
Intraventricular Infusions
Globus Pallidus
Enkephalins
Cytarabine
Bromodeoxyuridine
Tubulin
Substance P
Transgenic Mice
Regeneration
Stem Cells

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Cho, Sung-Rae ; Benraiss, Abdellatif ; Chmielnicki, Eva ; Samdani, Amer ; Economides, Aris ; Goldman, Steven A. / Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 10. pp. 2889-2902.
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Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. / Cho, Sung-Rae; Benraiss, Abdellatif; Chmielnicki, Eva; Samdani, Amer; Economides, Aris; Goldman, Steven A.

In: Journal of Clinical Investigation, Vol. 117, No. 10, 01.10.2007, p. 2889-2902.

Research output: Contribution to journalArticle

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