Polyglutamine tract‐binding protein‐1 dysfunction induces cell death of neurons through mitochondrial stress

• Published in: Journal of neurochemistry Vol. 95; no. 3; pp. 858 - 870
• Main Authors: Marubuchi, Shigeki, Wada, Yo‐ichi, Okuda, Tomohiro, Hara, Yukiko, Qi, Mei‐ling, Hoshino, Masataka, Nakagawa, Masaya, Kanazawa, Ichiro, Okazawa, Hitoshi
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.11.2005; Blackwell; Blackwell Publishing Ltd
• Subjects: Adenovirus; Ageing, cell death; Amino acids; Animals; Anterior Horn Cells - pathology; Anterior Horn Cells - physiology; Anterior Horn Cells - ultrastructure; Biological and medical sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caspases - metabolism; Cell Death - physiology; Cell physiology; Cells; Cerebrospinal fluid. Meninges. Spinal cord; Cytochromes c - metabolism; degeneration; Electron Transport Complex IV - metabolism; Fundamental and applied biological sciences. Psychology; Genetic research; Humans; Medical sciences; Membrane Potentials - physiology; Mice; Mice, Transgenic; Microscopy, Electron; Mitochondria - enzymology; Mitochondria - genetics; Mitochondria - ultrastructure; Molecular and cellular biology; Motor Neuron Disease - metabolism; Motor Neuron Disease - pathology; Motor Neuron Disease - physiopathology; Motor Neurons - pathology; Motor Neurons - physiology; Motor Neurons - ultrastructure; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; Nervous system (semeiology, syndromes); Neurological disorders; Neurology; neuron; Neurons; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oligonucleotide Array Sequence Analysis; Oxidative Stress - physiology; polyglutamine; polyglutamine tract‐binding protein‐1; Proteins; transcription; Transgenic animals; transgenic mouse; Up-Regulation - physiology; Spinal cord; transcription; Central nervous system; Motor neuron disease; Electrophysiology; neuron; Motor neuron; transgenic mouse; Binding protein; Mitochondria; Degenerative disease; Degeneration; Human; Nervous system diseases; Rodentia; Gene expression; polyglutamine; Stress; Vertebrata; Phenotype; Mammalia; Mouse; Cell death; Dysfunction; Central nervous system disease; polyglutamine tract-binding protein-1; Spinal cord disease; Nuclear protein
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03405.x

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.