title: Conophylline protects cells in cellular models of neurodegenerative diseases by inducing mammalian target of rapamycin (mTOR)-independent autophagy.
abstract: Macroautophagy is a cellular response that leads to the bulk, nonspecific degradation of cytosolic components, including organelles. In recent years, it has been recognized that autophagy is essential for prevention of neurodegenerative diseases, including Parkinson disease (PD) and Huntington disease (HD). Here, we show that conophylline (CNP), a vinca alkaloid, induces autophagy in an mammalian target of rapamycin-independent manner. Using a cellular model of PD, CNP suppressed protein aggregation and protected cells from cell death caused by treatment with 1-methyl-4-phenylpyridinium, a neurotoxin, by inducing autophagy. Moreover, in the HD model, CNP also eliminated mutant huntingtin aggregates. Our findings demonstrate the possible use of CNP as a therapeutic drug for neurodegenerative disorders, including PD and HD.
authors.affiliation: From the Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan and.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sasazawa
authors.affiliation: From the Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan and.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Sato
authors.affiliation: the Department of Molecular Target Medicine Screening, Aichi Medical University School of Medicine, Aichi 480-1195, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.affiliation: From the Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan and simizu@applc.keio.ac.jp.
authors.forename: Siro
authors.initials: S
authors.lastname: Simizu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020011:Protective Agents / Q000008:administration & dosage; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014748:Vinca Alkaloids / Q000008:administration & dosage*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D020011:Protective Agents; D014748:Vinca Alkaloids; C099167:conophylline; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Aggresome; Autophagy; Conophylline; Huntington Disease; Parkinson Disease; Protein Degradation