TDP-43 depletion induces neuronal cell damage through dysregulation of Rho family GTPases.
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.
Iguchi
Yohei
Y
Departments of Neurology, Showa-ku, Nagoya 466-8550.
Katsuno
Masahisa
M
Departments of Neurology, Showa-ku, Nagoya 466-8550; Institute for Advanced Research, Nagoya University, Nagoya 464-8601.
Niwa
Jun-Ichi
JI
Stroke Center, Aichi Medical University, Aichi 480-1195.
Yamada
Shin-Ichi
SI
Departments of Neurology, Showa-ku, Nagoya 466-8550.
Sone
Jun
J
Departments of Neurology, Showa-ku, Nagoya 466-8550.
Waza
Masahiro
M
Departments of Neurology, Showa-ku, Nagoya 466-8550.
Adachi
Hiroaki
H
Departments of Neurology, Showa-ku, Nagoya 466-8550.
Tanaka
Fumiaki
F
Departments of Neurology, Showa-ku, Nagoya 466-8550.
Nagata
Koh-Ichi
KI
Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Aichi 480-0838.
Arimura
Nariko
N
Tamagawa University Brain Science Institute, Tokyo 194-8610, Japan.
Watanabe
Takashi
T
Institute for Advanced Research, Nagoya University, Nagoya 464-8601; Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550.
Kaibuchi
Kozo
K
Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550.
Sobue
Gen
G
Departments of Neurology, Showa-ku, Nagoya 466-8550.
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
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