Integrated regulation of dopaminergic and epigenetic effectors of neuroprotection in Parkinson's disease models.

Whole-exome sequencing of Parkinson's disease (PD) patient DNA identified single-nucleotide polymorphisms (SNPs) in the tyrosine nonreceptor kinase-2 () gene. Although this kinase had a previously demonstrated activity in preventing the endocytosis of the dopamine reuptake transporter (DAT), a causal role for TNK2-associated dysfunction in PD remains unresolved. We postulated the dopaminergic neurodegeneration resulting from patient-associated variants in were a consequence of aberrant or prolonged TNK2 overactivity, the latter being a failure in TNK2 degradation by an E3 ubiquitin ligase, neuronal precursor cell-expressed developmentally down-regulated-4 (NEDD4).