title: p62 plays a protective role in the autophagic degradation of polyglutamine protein oligomers in polyglutamine disease model flies.
abstract: Oligomer formation and accumulation of pathogenic proteins are key events in the pathomechanisms of many neurodegenerative diseases, such as Alzheimer disease, ALS, and the polyglutamine (polyQ) diseases. The autophagy-lysosome degradation system may have therapeutic potential against these diseases because it can degrade even large oligomers. Although p62/sequestosome 1 plays a physiological role in selective autophagy of ubiquitinated proteins, whether p62 recognizes and degrades pathogenic proteins in neurodegenerative diseases has remained unclear. In this study, to elucidate the role of p62 in such pathogenic conditions in vivo, we used Drosophila models of neurodegenerative diseases. We found that p62 predominantly co-localizes with cytoplasmic polyQ protein aggregates in the MJDtr-Q78 polyQ disease model flies. Loss of p62 function resulted in significant exacerbation of eye degeneration in these flies. Immunohistochemical analyses revealed enhanced accumulation of cytoplasmic aggregates by p62 knockdown in the MJDtr-Q78 flies, similarly to knockdown of autophagy-related genes (Atgs). Knockdown of both p62 and Atgs did not show any additive effects in the MJDtr-Q78 flies, implying that p62 function is mediated by autophagy. Biochemical analyses showed that loss of p62 function delays the degradation of the MJDtr-Q78 protein, especially its oligomeric species. We also found that loss of p62 function exacerbates eye degeneration in another polyQ disease fly model as well as in ALS model flies. We therefore conclude that p62 plays a protective role against polyQ-induced neurodegeneration, by the autophagic degradation of polyQ protein oligomers in vivo, indicating its therapeutic potential for the polyQ diseases and possibly for other neurodegenerative diseases.
authors.affiliation: From the Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan, the Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8551, Japan, the Graduate School of Medical and Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, Chiba 260-8670, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Saitoh
authors.affiliation: From the Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Fujikake
authors.affiliation: From the Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Yuma
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: From the Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: H Akiko
authors.initials: HA
authors.lastname: Popiel
authors.affiliation: From the Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hatanaka
authors.affiliation: From the Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Ueyama
authors.affiliation: From the Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: the Laboratoire de Génétique et Biologie Cellulaire, EA4589, Université de Versailles-Saint-Quentin-en-Yvelines, École Pratique des Hautes Etudes, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France, and.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gaumer
authors.affiliation: the Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8551, Japan, the Graduate School of Medical and Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, Chiba 260-8670, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Murata
authors.affiliation: From the Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.affiliation: From the Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan nagai@ncnp.go.jp.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagai
mesh_terms: D000818:Animals; D001343:Autophagy; D003593:Cytoplasm / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D008855:Microscopy, Electron, Scanning; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry*; D010766:Phosphorylation; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism* / Q000648:ultrastructure; D011489:Protein Denaturation; D017510:Protein Folding; D035381:TATA-Binding Protein Associated Factors / Q000378:metabolism*; D035362:Transcription Factor TFIID / Q000378:metabolism*; D019076:Transgenes; D057149:Ubiquitinated Proteins / Q000737:chemistry
chemical_list: D029721:Drosophila Proteins; D010455:Peptides; D035381:TATA-Binding Protein Associated Factors; C084976:Taf6 protein, Drosophila; D035362:Transcription Factor TFIID; D057149:Ubiquitinated Proteins; C097188:polyglutamine
keywords: Autophagy; Drosophila; Neurodegenerative Disease; Oligomer; Polyglutamine Disease; Protein Aggregation; p62