title: AAV1/2-mediated BDNF gene therapy in a transgenic rat model of Huntington's disease.
abstract: Reduced expression and disrupted corticostriatal transportation of brain-derived neurotrophic factor (BDNF) is proposed to contribute to the selective vulnerability of medium spiny striatal projection neurons (MSNs) in Huntington's disease (HD). We have previously demonstrated that BDNF overexpression in the quinolinic acid lesioned rat striatum attenuates motor impairment and reduces the extent of MSN cell loss. To further investigate the potential therapeutic properties of BDNF for HD, the current study examines the effect of bilateral AAV1/2-mediated BDNF expression in the striatum of a transgenic rat model of HD. Transfer of the BDNF gene to striatal neurons using an AAV1/2 serotype vector enhanced BDNF protein levels in the striatum. Bilateral BDNF expression attenuated the impairment of both motor and cognitive function when compared with AAV1/2-vehicle- or YFP-treated transgenic HD rats. Interestingly, a gender effect was apparent with female transgenic HD rats exhibiting less functional impairment than males. Quantification of NeuN and DARRP32 immunoreactivity and striatal volume revealed limited disease phenotype between wild type and transgenic HD animals. However, AAV1/2-BDNF-treated transgenic HD rats showed evidence of greater striatal volume and increased NeuN+ cell numbers compared with wild-type vehicle- and AAV1/2-vehicle- or YFP-treated transgenic HD rats. We propose BDNF holds considerable therapeutic potential for alleviating behavioral dysfunction and neuronal degeneration in HD, with further work required to examine the role of BDNF-TrkB signaling and the preservation of axonal and synaptic function.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: B
authors.initials: B
authors.lastname: Connor
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: D
authors.initials: D
authors.lastname: von Hieber
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: S K
authors.initials: SK
authors.lastname: Tang
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: K S
authors.initials: KS
authors.lastname: Jones
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: C
authors.initials: C
authors.lastname: Maucksch
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000503:physiopathology*; D000229:Dependovirus / Q000235:genetics; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006816:Huntington Disease / Q000235:genetics* / Q000628:therapy*; D008297:Male; D023421:Models, Animal; D051381:Rats
chemical_list: D019208:Brain-Derived Neurotrophic Factor