Authors:
Michaeline L. Hebron, Irina Lonskaya, Kaydee Sharpe, Puwakdandawe P. K. Weerasinghe, Norah K. Algarzae, Ashot R. Shekonyan, and Charbel E. H. Moussa
Summary:
The importance of E3 ubiquitin ligases, involved in 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, while parkin co-expression mediated K48 and K63-linked ubiquitin to TDP-43 and led to cytosolic co-localization of parkin with ubiquitinated TDP-43. Parkin and TDP-43 formed a multi-protein complex with HDAC6, perhaps to mediate TDP-43 translocation. In conclusion, parkin ubiquitinates TDP-43 and facilitates its cytosolic accumulation through a multi-protein complex with HDAC6.
Source:
The Journal of Biological Chemistry; (12/20/12)