Hebron ML, Lonskaya I, Sharpe K, Weerasinghe PP, Algarzae NK, Shekonyan AR, Moussa CE

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. ...

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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.

Date: Dec. 20, 2012

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