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.

Diminished parkin solubility and co-localization with intraneuronal amyloid-ß are associated with autophagic defects in Alzheimer's disease.

Alzheimer's disease (AD) is an aging disorder characterized by amyloid-ß (Aß) accumulation in extracellular plaques and formation of intracellular tangles containing hyperphosphorylated tau (p-Tau). Autophagic defects, leading to accumulation of autophagosomes, are recognized in AD. Parkin is an E3 ubiquitin ligase involved in degradation of proteins via autophagy and the proteasome. We investigated the role of parkin in postmortem brain tissues from 21 AD patients and 15 control subjects. We detected decreased parkin solubility in AD cortex and parkin co-localization with intraneuronal Aß(1-42) in the hippocampus and cortex of AD patients. Parkin accumulation with intraneuronal Aß and p-Tau was detected in autophagosomes in AD brains. To determine the role of parkin in Aß clearance, we generated gene transfer animals expressing lentiviral Aß(1-42)with and without parkin and examined autophagic mechanisms. Lentiviral expression of Aß(1-42) led to p-Tau accumulation and induced autophagic defects, leading to accumulation of autophagic vacuoles. However, co-expression of wild type parkin facilitated autophagic clearance and promoted deposition of Aß(1-42) and p-Tau into the lysosome. Taken together, these data suggest that Aß(1-42) alters normal autophagy and parkin enhances autophagic clearance. In conclusion, decreased parkin solubility may lead to co-localization with intraneuronal Aß(1-42) and compromise the cell autophagic clearance ability. Parkin may clear autophagic defects via autophagosome degradation.