p62 Plays a Protective Role in the Autophagic Degradation of Polyglutamine Protein Oligomers in Polyglutamine Disease Model Flies

• Published in: The Journal of biological chemistry Vol. 290; no. 3; pp. 1442 - 1453
• Main Authors: Saitoh, Yuji, Fujikake, Nobuhiro, Okamoto, Yuma, Popiel, H. Akiko, Hatanaka, Yusuke, Ueyama, Morio, Suzuki, Mari, Gaumer, Sébastien, Murata, Miho, Wada, Keiji, Nagai, Yoshitaka
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.01.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Autophagy; Cytoplasm - metabolism; Drosophila; Drosophila Proteins - metabolism; Immunohistochemistry; Microscopy, Electron, Scanning; Molecular Bases of Disease; Neurodegenerative Disease; Neurodegenerative Diseases - metabolism; Oligomer; p62; Peptides - chemistry; Phosphorylation; Photoreceptor Cells, Invertebrate - metabolism; Photoreceptor Cells, Invertebrate - ultrastructure; Polyglutamine Disease; Protein Aggregation; Protein Denaturation; Protein Folding; TATA-Binding Protein Associated Factors - metabolism; Transcription Factor TFIID - metabolism; Transgenes; Ubiquitinated Proteins - chemistry; Neurodegenerative Disease; Protein Aggregation; Drosophila; Polyglutamine Disease; Oligomer; Autophagy; p62
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.590281

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.Oligomers of pathogenic proteins are implicated in the pathomechanisms of neurodegenerative diseases. Depletion of p62 delays the degradation of polyglutamine protein oligomers via autophagy and exacerbates neurodegeneration in polyglutamine disease model flies. p62 plays a protective role via autophagic degradation of polyglutamine protein oligomers. p62 should be a therapeutic target for the polyglutamine diseases.