title: Polyglutamine tract-binding protein-1 dysfunction induces cell death of neurons through mitochondrial stress.
abstract: Polyglutamine tract-binding protein-1 (PQBP-1) is a nuclear protein that interacts and colocalizes with mutant polyglutamine proteins. We previously reported that PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype and cell death of motor neurons analogous to human neurodegeneration. To investigate the molecular mechanisms underlying the motor neuron death, we performed microarray analyses using the anterior horn tissues of the spinal cord and compared gene expression profiles between pre-symptomatic transgenic and age-matched control mice. Surprisingly, half of the spots changed more than 1.5-fold turned out to be genes transcribed from the mitochondrial genome. Northern and western analyses confirmed up-regulation of representative mitochondrial genes, cytochrome c oxidase (COX) subunit 1 and 2. Immunohistochemistry revealed that COX1 and COX2 proteins are increased in spinal motor neurons. Electron microscopic analyses revealed morphological abnormalities of mitochondria in the motor neurons. PQBP-1 overexpression in primary neurons by adenovirus vector induced abnormalities of mitochondrial membrane potential from day 5, while cytochrome c release and caspase 3 activation were observed on day 9. An increase of cell death by PQBP-1 was also confirmed on day 9. Collectively, these results indicate that dysfunction of PQBP-1 induces mitochondrial stress, a key molecular pathomechanism that is shared among human neurodegenerative disorders.
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center of Excellence Program (COE) for Brain Integration and Its Disorders, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Marubuchi
authors.forename: Yo-Ichi
authors.initials: Y
authors.lastname: Wada
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Okuda
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hara
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Qi
authors.forename: Masataka
authors.initials: M
authors.lastname: Hoshino
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kanazawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa
mesh_terms: D000818:Animals; D000870:Anterior Horn Cells / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics* / Q000648:ultrastructure; D016472:Motor Neuron Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C119246:PQBP1 protein, human; D045304:Cytochromes c; D003576:Electron Transport Complex IV; D020169:Caspases