title: TDP-43 depletion induces neuronal cell damage through dysregulation of Rho family GTPases.
abstract: The 43-kDa TAR DNA-binding protein (TDP-43) is known to be a major component of the ubiquitinated inclusions characteristic of amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Although TDP-43 is a nuclear protein, it disappears from the nucleus of affected neurons and glial cells, implicating TDP-43 loss of function in the pathogenesis of neurodegeneration. Here we show that the knockdown of TDP-43 in differentiated Neuro-2a cells inhibited neurite outgrowth and induced cell death. In knockdown cells, the Rho family members RhoA, Rac1, and Cdc42 GTPases were inactivated, and membrane localization of these molecules was reduced. In addition, TDP-43 depletion significantly suppressed protein geranylgeranylation, a key regulating factor of Rho family activity and intracellular localization. In contrast, overexpression of TDP-43 mitigated the cellular damage caused by pharmacological inhibition of geranylgeranylation. Furthermore administration of geranylgeranyl pyrophosphate partially restored cell viability and neurite outgrowth in TDP-43 knockdown cells. In summary, our data suggest that TDP-43 plays a key role in the maintenance of neuronal cell morphology and survival possibly through protein geranylgeranylation of Rho family GTPases.
authors.affiliation: Departments of Neurology, Showa-ku, Nagoya 466-8550.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Iguchi
authors.affiliation: Departments of Neurology, Showa-ku, Nagoya 466-8550; Institute for Advanced Research, Nagoya University, Nagoya 464-8601.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Stroke Center, Aichi Medical University, Aichi 480-1195.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Niwa
authors.affiliation: Departments of Neurology, Showa-ku, Nagoya 466-8550.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Yamada
authors.affiliation: Departments of Neurology, Showa-ku, Nagoya 466-8550.
authors.forename: Jun
authors.initials: J
authors.lastname: Sone
authors.affiliation: Departments of Neurology, Showa-ku, Nagoya 466-8550.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Waza
authors.affiliation: Departments of Neurology, Showa-ku, Nagoya 466-8550.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Adachi
authors.affiliation: Departments of Neurology, Showa-ku, Nagoya 466-8550.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Aichi 480-0838.
authors.forename: Koh-Ichi
authors.initials: KI
authors.lastname: Nagata
authors.affiliation: Tamagawa University Brain Science Institute, Tokyo 194-8610, Japan.
authors.forename: Nariko
authors.initials: N
authors.lastname: Arimura
authors.affiliation: Institute for Advanced Research, Nagoya University, Nagoya 464-8601; Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550.
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.affiliation: Departments of Neurology, Showa-ku, Nagoya 466-8550.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: D004268:DNA-Binding Proteins; D009479:Neuropeptides; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; D020169:Caspases; C526380:RhoA protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein