title: Mutant Huntingtin induces activation of the Bcl-2/adenovirus E1B 19-kDa interacting protein (BNip3).
abstract: Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive neuronal death in the basal ganglia and cortex. Although increasing evidence supports a pivotal role of mitochondrial dysfunction in the death of patients' neurons, the molecular bases for mitochondrial impairment have not been elucidated. We provide the first evidence of an abnormal activation of the Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNip3) in cells expressing mutant Huntingtin. In this study, we show an abnormal accumulation and dimerization of BNip3 in the mitochondria extracted from human HD muscle cells, HD model cell cultures and brain tissues from HD model mice. Importantly, we have shown that blocking BNip3 expression and dimerization restores normal mitochondrial potential in human HD muscle cells. Our data shed light on the molecular mechanisms underlying mitochondrial dysfunction in HD and point to BNip3 as a new potential target for neuroprotective therapy in HD.
authors.affiliation: Department of Neurology and Laboratory of Neuroscience, Centro Dino Ferrari Università degli Studi di Milano-IRCCS Istituto Auxologico Italiano, Milano, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Sassone
authors.forename: C
authors.initials: C
authors.lastname: Colciago
authors.forename: P
authors.initials: P
authors.lastname: Marchi
authors.forename: C
authors.initials: C
authors.lastname: Ascardi
authors.forename: L
authors.initials: L
authors.lastname: Alberti
authors.forename: A
authors.initials: A
authors.lastname: Di Pardo
authors.forename: R
authors.initials: R
authors.lastname: Zippel
authors.forename: S
authors.initials: S
authors.lastname: Sipione
authors.forename: V
authors.initials: V
authors.lastname: Silani
authors.forename: A
authors.initials: A
authors.lastname: Ciammola
mesh_terms: D000818:Animals; D002460:Cell Line; D019281:Dimerization; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000032:analysis / Q000378:metabolism*; D032342:Muscle Cells / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism*
chemical_list: C090121:BNIP3 protein, human; C508686:BNip3 protein, mouse; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins