title: Dynein and dynactin components modulate neurodegeneration induced by excitotoxicity.
abstract: Glutamate excitotoxicity causes neuronal dysfunction and degeneration. It is implicated in chronic disorders, including Alzheimer's disease, and in acute CNS insults such as ischemia. These disorders share prominent morphological features, including axon degeneration and cell body death. However, the molecular mechanism underlying excitotoxicity-induced neurodegeneration remains poorly understood. A key molecular feature of neurodegeneration is deficits in microtubule-based cargo transport that plays a pivotal role in maintaining the balance of survival and stress signaling in the axon. We developed an excitotoxicity-induced neurodegeneration system in primary neuronal cultures. We find that excitotoxicity generates a C-terminal truncated form of p150Glued, a major component of the dynactin complex, which exacerbates axon degeneration. This p150Glued truncated form was identified in brain tissues of patients with Alzheimer's disease. Overexpression of wild-type (WT) dynein intermediate chain (DIC), a dynein component that interacts with p150Glued and links dynein and dynactin complexes, DIC (S84D) mutant, and WT p150Glued suppressed axon degeneration. These modulating effects of p150Glued and DIC on excitotoxicity-induced axon degeneration are also observed in apoptosis and cell body death. Thus, our findings identify retrograde transport proteins, p150Glued and DIC, as novel modulators of neurodegeneration induced by glutamate excitotoxicity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, Osaka, Japan. fujiwara@anat3.med.osaka-u.ac.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Koji
authors.initials: K
authors.lastname: Morimoto
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001369:Axons / Q000187:drug effects; D002478:Cells, Cultured; D000072159:Dynactin Complex; D004398:Dyneins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D004622:Embryo, Mammalian; D018846:Excitatory Amino Acids / Q000633:toxicity*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000633:toxicity*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D000072159:Dynactin Complex; D018846:Excitatory Amino Acids; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C485184:enhanced green fluorescent protein; C085348:tau-1 monoclonal antibody; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D004398:Dyneins