Clusions of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, which was initially identified due to its specific enrichment in the detergent-insoluble biochemical fraction of FTLD frontal cortex. Although physiological TDP-43 is a predominantly nuclear protein with the capacity to transiently shuttle to and from the cytoplasm in a manner dependent upon general transcription, pathological TDP-43 redistributes from the nucleus to the cytoplasm where it more often aggregates following phosphorylation, ubiquitination and proteolytic cleavage. Despite recent progress in demonstrating that TDP-43 C-terminal fragments aggregate in cytoplasm in relative absence of RNA or dynein-dependent transport, a comprehensive understanding of molecular mechanisms that determine or ensue from TDP-43 aggregation remains elusive. In contrast, a potential naturally occurring human 33.5 kDa N-terminal splicing variant of TDP-43 displays prominent cytoplasmic aggregation and post-translational modification upon over-expression, recapitulating disease phenotype. The splicing event leading to TDP-S6 mRNA detected in mouse skips the large, evolutionarily conserved 59 exon encoding the glycine-rich C-terminus of full length TDP-43 which is itself responsible for promoting exon skipping events in splicing, and leads to utilization of a highly conserved alternative exon with a premature stop codon. Like the mouse isoform, human TDP-S6 has 18 unique amino acids at its Cterminus and is 295 LY294002 residues in total compared to the full length protein with 414 residues. The detergent-insoluble biochemical fraction for TDP-S6 expressing cells accumulated ubiquitin and SUMO2 or SUMO3 conjugates at high-molecular weights, whereas the same fraction from TDP-43 overexpressing cells showed only an increase in SUMO2/3. Compared to TDPS6, TDP-43 was more robustly phosphorylated in western blots, consistent with phosphorylation on two C-terminal serine residues only present in TDP-43. It is unknown if TDP-43- or TDP-S6-associated post-translational modifications play a role in the mechanism underlying TDP-43 proteinopathy because precise identification of PTM sites and PTM involvement in recruiting interaction partners to biochemically insoluble aggregates with TDP-43 remains largely unexplored. Mechanisms of TDP-43 aggregation defined in cellular models, particularly determinants in terms of primary structure motifs and PTMs on TDP-43 or partners could provide insight into pathology in more complex tissues. PTMs generally influence protein-protein, protein-nucleic acid, and/or protein-membrane interactions by altering or augmenting the protein surfaces available for stable interactions with select PTMsensitive or PTM-dependent partners. For example, ubiquitination of a protein can enable interactions with ubiquitin receptors facilitating aggresome formation, or with other receptors that drive protein flux through the proteasome, or at autophagosomes accumulating proteins for degradation. The purpose of this study was to determine what interactions with TDP-43 or TDP-S6 occur in detergent-resistant.