title: Propagation of dysbindin-1B aggregates: exosome-mediated transmission of neurotoxic deposits.
abstract: Given the detection of aggregated deposits in chronic mental diseases (CMD), the disturbance of proteostasis in those diseases is receiving increasing attention. The study of aggregated proteins can contribute to our understanding of the chronic and progressive condition of such diseases. Dysbindin, encoded by the schizophrenia susceptibility gene DTNBP1, has been reported to co-aggregate with DISC1. However, there has been no evidence to date on the aggregation tendency of dysbindin. Therefore, we investigated the isoform-specific aggregation of dysbindin. We found that dysbindin-1B aggregated into cell-invasive deposits in mice. Because of the efficient propagation of dysbindin-1B, we further studied the mechanism of propagation and identified it as exosome-mediated transmission of the aggregates. In addition, aggregates of dysbindin-1B were toxic. Through exosome-mediated propagation, the deposits of dysbindin-1B exerted toxic effects on recipient neurons a long distance away from the initial aggregation site in mice brain. The rapid long distance propagation of neurotoxic deposits of dysbindin-1B in affected neuronal circuitry indicates a possible mechanism for the progressive deterioration of neurons and cognitive function in CMD.
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, PR China.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Zhu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shen
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, PR China. Electronic address: qixu@vip.sina.com.
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D066329:Protein Aggregates / Q000502:physiology; D066263:Protein Aggregation, Pathological; D014162:Transfection
chemical_list: C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D066329:Protein Aggregates
keywords: aggregation; chronic mental diseases; dysbindin; neurotoxicity; propagation