title: Progressive loss of BDNF in a mouse model of Huntington's disease and rescue by BDNF delivery.
abstract: Huntingtin is a protein of 348 kDa that is mutated in Huntington's disease (HD), a dominantly inherited neurodegenerative disorder. Previous data have led us to propose that aspects of the disease arise from both a loss of the neuroprotective function of the wild-type protein, and a toxic activity gained by the mutant protein. In particular, we have shown that wild-type huntingtin stimulates the production of brain-derived neurotrophic factor (BDNF), a pro-survival factor for the striatal neurons that die in the pathology. Wild-type huntingtin controls BDNF gene transcription in cerebral cortex, which is then delivered to its striatal targets. In the disease state, supply of cortical BDNF to the striatum is strongly reduced, possibly leading to striatal vulnerability. Here we show that a reduction in cortical BDNF messenger level correlates with the progression of the disease in a mouse model of HD. In particular, we show that the progressive loss of mRNAs transcribed from BDNF exon II, III and IV follows a different pattern that may reflect different upstream mechanisms impaired by mutation in huntingtin. On this basis, we also discuss the possibility that delivery of BDNF may represent an useful strategy for Huntington's disease treatment.
authors.affiliation: Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9, 20133 Milano, Italy. chiara.zuccato@unimi.it
authors.forename: Chiara
authors.initials: C
authors.lastname: Zuccato
authors.forename: Daniel
authors.initials: D
authors.lastname: Liber
authors.forename: Catarina
authors.initials: C
authors.lastname: Ramos
authors.forename: Alessia
authors.initials: A
authors.lastname: Tarditi
authors.forename: Dorotea
authors.initials: D
authors.lastname: Rigamonti
authors.forename: Marzia
authors.initials: M
authors.lastname: Tartari
authors.forename: Marta
authors.initials: M
authors.lastname: Valenza
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger