We noted that TDP-S6 aggregate proteins were less enriched than with TDP-43 overexpression, despite the fact that TDP-specific peptides were more enriched in the TDP-S6 model. We therefore asked what the identities are of the proteins that are at least moderately enriched and are more enriched in the TDPS6 model. Surprisingly, this short list of 22 proteins is populated by no fewer than ten proteins known to participate in cytoplasmic stress granules. An eleventh protein, PA2G4/EBP1, similar to eIF4A and GNB2L1/RACK1 in Table 1 group 2, has a role in modulating translation initiation complex assembly, in this case via inhibition of eIF2a phosphorylation, posing the possibility that overexpressed TDP-S6 interacts with PA2G4 and could alter kinase signaling that accelerates assembly of eIF2-RNA binding-ribosome preinitiation Nilotinib Src-bcr-Abl inhibitor complexes, thereby modulating translation rate for some mRNAs, while cytoplasmic stress granule assembly in response to many stresses is also strongly influenced by eIF2a phosphorylation. Consistent with eIF2 complex absence from stress granule-associated preinitiation complexes, the three eIF2 complex members were quantified by multiple peptide ratios in the second replicate with spiked-in RIPA-soluble standard, with no increase evident in the TDP-S6 model aggregate proteome. However, a peptide specific to other TDP-43 isoforms excluding TDP-S6 increased significantly more than the TDP-S6 specific peptide, similar to a shared N-terminal peptide residing in both full length TDP-43 and TDP-S6 RRM1. In contrast, with TDP-S6 overexpression, the TDP-S6 peptide increased 60-fold, and the peptide that is specific for non-TDP-S6 splice isoforms increased to an extent similar to the levels seen with arsenite treatment. These results indicate that endogenous TDP-S6 may also participate in arsenite-induced detergent-insoluble cellular features along with TDP-43. The most likely candidate for such features is stress granules. One explanation for the significantly less robust increase in TDP-S6 than other TDP-43 isoforms with arsenite treatment could be the intrinsic low abundance of TDP-S6 relative to other isoforms; indeed, a rough comparison of relative abundance provided by the average raw signal intensity for each of the two exon junction peptides suggests a stoichiometry of 20:3 for endogenous TDP-43:TDP-S6, even in the arsenite treated insoluble fraction. Moreover, no increase in mature TDP-S6 splicing product is evident via reverse transcriptase PCR of RNA from 1.5 h arsenite-treated HEK-293 cells relative to controls, although the mRNA for full length TDP-43 appears to decrease in abundance, either due to increased splicing of other isoforms, a decrease in transcription from the TARDBP locus, or destabilization of existing TDP-43 mRNA, any of which might promote the later resolution of stress granules, since TDP-43 stabilizes them. We conclude that there is a possibility that any increase in total TDP-S6 due to arsenite could be a result of enhanced translation or stability of existing TDP-S6 mRNA.