Parkin Ubiquitinates Tar-DNA Binding Protein-43 (TDP-43) and Promotes Its Cytosolic Accumulation via Interaction with Histone Deacetylase 6 (HDAC6)

The importance of E3 ubiquitin ligases, involved in the degradation of misfolded proteins or promotion of protein-protein interaction, is increasingly recognized in neurodegeneration. TDP-43 is a predominantly nuclear protein, which regulates the transcription of thousands of genes and binds to mRNA of the E3 ubiquitin ligase Parkin to regulate its expression. Wild type and mutated TDP-43 are detected in ubiquitinated forms within the cytosol in several neurodegenerative diseases. We elucidated the mechanisms of TDP-43 interaction with Parkin using transgenic A315T mutant TDP-43 (TDP43-Tg) mice, lentiviral wild type TDP-43, and Parkin gene transfer rat models. TDP-43 expression increased Parkin mRNA and protein levels. Lentiviral TDP-43 increased the levels of nuclear and cytosolic protein, whereas Parkin co-expression mediated Lys-48 and Lys-63-linked ubiquitin to TDP-43 and led to cytosolic co-localization of Parkin with ubiquitinated TDP-43. Parkin and TDP-43 formed a multiprotein complex with HDAC6, perhaps to mediate TDP-43 translocation. In conclusion, Parkin ubiquitinates TDP-43 and facilitates its cytosolic accumulation through a multiprotein complex with HDAC6. Background: TDP-43 pathology and the role of E3 ubiquitin ligases are increasingly recognized in neurodegeneration. Results: Parkin ubiquitinates TDP-43 and forms a multiprotein complex with HDAC6 to sequester TDP-43 in cytosol. Conclusion: Parkin E3 ubiquitin ligase activity promotes TDP-43 inclusion formation and nuclear translocation. Significance: Parkin-TDP-43 interaction may be exploited as a therapeutic strategy in ALS/FTLD pathology.