title: C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress.
abstract: BACKGROUND
  TDP-43 proteinopathies are characterized by loss of nuclear TDP-43 expression and formation of C-terminal TDP-43 fragmentation and accumulation in the cytoplasm. Recent studies have shown that TDP-43 can accumulate in RNA stress granules (SGs) in response to cell stresses and this could be associated with subsequent formation of TDP-43 ubiquinated protein aggregates. However, the initial mechanisms controlling endogenous TDP-43 accumulation in SGs during chronic disease are not understood. In this study we investigated the mechanism of TDP-43 processing and accumulation in SGs in SH-SY5Y neuronal-like cells exposed to chronic oxidative stress. Cell cultures were treated overnight with the mitochondrial inhibitor paraquat and examined for TDP-43 and SG processing.
  
  
  RESULTS
  We found that mild stress induced by paraquat led to formation of TDP-43 and HuR-positive SGs, a proportion of which were ubiquitinated. The co-localization of TDP-43 with SGs could be fully prevented by inhibition of c-Jun N-terminal kinase (JNK). JNK inhibition did not prevent formation of HuR-positive SGs and did not prevent diffuse TDP-43 accumulation in the cytosol. In contrast, ERK or p38 inhibition prevented formation of both TDP-43 and HuR-positive SGs. JNK inhibition also inhibited TDP-43 SG localization in cells acutely treated with sodium arsenite and reduced the number of aggregates per cell in cultures transfected with C-terminal TDP-43 162-414 and 219-414 constructs.
  
  
  CONCLUSIONS
  Our studies are the first to demonstrate a critical role for kinase control of TDP-43 accumulation in SGs and may have important implications for development of treatments for FTD and ALS, targeting cell signal pathway control of TDP-43 aggregation.
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria, 3010, Australia. arwhite@unimelb.edu.au.
authors.forename: Jodi
authors.initials: J
authors.lastname: Meyerowitz
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Parker
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Vella
authors.forename: Dominic Ch
authors.initials: DCh
authors.lastname: Ng
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Price
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Liddell
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Caragounis
authors.forename: Qiao-Xin
authors.initials: QX
authors.lastname: Li
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Masato
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authors.lastname: Hasegawa
authors.forename: Marie A
authors.initials: MA
authors.lastname: Bogoyevitch
authors.forename: Katja M
authors.initials: KM
authors.lastname: Kanninen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White