Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, motor neuron 
disease with no effective long-term treatment options. Recently, TDP-43 has been 
identified as a key protein in the pathogenesis of some cases of ALS. Although 
the role of TDP-43 in motor neuron degeneration is not yet known, TDP-43 has 
been shown to accumulate in RNA stress granules (SGs) in cell models and in 
spinal cord tissue from ALS patients. The SG association may be an early 
pathological change to TDP-43 metabolism and as such a potential target for 
therapeutic intervention. Accumulation of TDP-43 in SGs induced by inhibition of 
mitochondrial activity can be inhibited by modulation of cellular kinase 
activity. We have also found that treatment of cells and animal models of 
neurodegeneration, including an ALS model, with bioavailable 
bis(thiosemicarbazonato)copper(II) complexes (Cu(II)(btsc)s) can modulate kinase 
activity and induce neuroprotective effects. In this study we examined the 
effect of diacetylbis(-methylthiosemicarbazonato)copper(II) (Cu(II)(atsm)) and 
glyoxalbis(-methylthiosemicarbazonato)copper(II) (Cu(II)(gtsm)) on 
TDP-43-positive SGs induced in SH-SY5Y cells in culture. We found that the 
Cu(II)(btsc)s blocked formation of TDP-43-and human antigen R (HuR)-positive SGs 
induced by paraquat. The Cu(II)(btsc)s protected neurons from paraquat-mediated 
cell death. These effects were associated with inhibition of ERK 
phosphorylation. Co-treatment of cultures with either Cu(II)(atsm) or an ERK 
inhibitor, PD98059 both prevented ERK activation and blocked formation of 
TDP-43-and HuR-positive SGs. Cu(II)(atsm) treatment or ERK inhibition also 
prevented abnormal ubiquitin accumulation in paraquat-treated cells suggesting a 
link between prolonged ERK activation and abnormal ubiquitin metabolism in 
paraquat stress and inhibition by Cu. Moreover, Cu(II)(atsm) reduced 
accumulation of C-terminal (219-414) TDP-43 in transfected SH-SY5Y cells. These 
results demonstrate that Cu(II)(btsc) complexes could potentially be developed 
as a neuroprotective agent to modulate neuronal kinase function and inhibit 
TDP-43 aggregation. Further studies in TDP-43 animal models are warranted.