Dual-specificity tyrosine-regulated kinases (DYRKs) comprise a family of protein kinases within the CMGC group of the eukaryotic kinome. Members of the DYRK family are found in 4 (animalia, plantae, fungi, and protista) of the 5 main taxa or kingdoms, and all DYRK proteins studied to date share common structural, biochemical, and functional properties with their ancestors in yeast. Recent work on DYRK proteins indicates that they participate in several signaling pathways critical for developmental processes and cell homeostasis. In this review, we focus on the DYRK family of proteins from an evolutionary, biochemical, and functional point of view and discuss the most recent, relevant, and controversial contributions to the study of these kinases.

In Parkinson’s disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD.

The trophic response of dopamine neurons to GDNF, mediated by the transcription factor Nurr1, protects them from α-synuclein–mediated toxicity.