title: ALS/FTLD-linked TDP-43 regulates neurite morphology and cell survival in differentiated neurons.
abstract: Tar-DNA binding protein of 43kDa (TDP-43) has been characterized as a major component of protein aggregates in brains with neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, physiological roles of TDP-43 and early cellular pathogenic effects caused by disease associated mutations in differentiated neurons are still largely unknown. Here, we investigated the physiological roles of TDP-43 and the effects of missense mutations associated with diseases in differentiated cortical neurons. The reduction of TDP-43 by siRNA increased abnormal neurites and decreased cell viability. ALS/FTLD-associated missense mutant proteins (A315T, Q331K, and M337V) were partially mislocalized to the cytosol and neurites when compared to wild-type and showed abnormal neurites similar to those observed in cases of loss of TDP-43. Interestingly, cytosolic expression of wild-type TDP-43 with mutated nuclear localization signals also induced abnormal neurtie morphology and reduction of cell viability. However, there was no significant difference in the effects of cytosolic expression in neuronal morphology and cell toxicity between wild-type and missense mutant proteins. Thus, our results suggest that mislocalization of missense mutant TDP-43 may contribute to loss of TDP-43 function and affect neuronal morphology, probably via dominant negative action before severe neurodegeneration in differentiated cortical neurons.
authors.affiliation: Department of Biotechnology, College of Life Science and Nanotechnology, Hannam University, Dajeon 305-811, Republic of Korea.
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Han
authors.affiliation: Department of Biotechnology, College of Life Science and Nanotechnology, Hannam University, Dajeon 305-811, Republic of Korea.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Yu
authors.affiliation: Department of Biotechnology, College of Life Science and Nanotechnology, Hannam University, Dajeon 305-811, Republic of Korea.
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Ryu
authors.affiliation: Department of Biotechnology, College of Life Science and Nanotechnology, Hannam University, Dajeon 305-811, Republic of Korea.
authors.forename: Mi-Hee
authors.initials: MH
authors.lastname: Jun
authors.affiliation: Department of Biotechnology, College of Life Science and Nanotechnology, Hannam University, Dajeon 305-811, Republic of Korea.
authors.forename: Byung-Kwan
authors.initials: BK
authors.lastname: Ban
authors.affiliation: Department of Applied Biology, College of Ecology and Environment, Kyungpook National University, 386, Gajang-dong, Sangju-si, Kyungbuk 742-711, Republic of Korea.
authors.forename: Deok-Jin
authors.initials: DJ
authors.lastname: Jang
authors.affiliation: Department of Biotechnology, College of Life Science and Nanotechnology, Hannam University, Dajeon 305-811, Republic of Korea. Electronic address: leeja@hnu.kr.
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Lee
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D048430:Cell Shape / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004622:Embryo, Mammalian; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D020125:Mutation, Missense / Q000502:physiology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D021381:Protein Transport / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins
keywords: ALS; Cell survival; FTD; Neurite; TDP-43