Characterization of VRK1 mutants implicated in human neurodegenerative diseases

Resumen del trabajo presentado en el 41 Congreso de la SEBBM (Sociedad Española de Bioquímica y Biología Molecular), celebrado en Santander (España) del 10 al 13 de septiembre de 2018.VRK1 is a nuclear and chromatin Ser-Thr kinase that appeared late in evolution. VRK1 gene expression is ubiquitous, and it is highly expressed in proliferating cells, and in many tumours associated to a poorer prognosis. VRK1 participates in several processes that include regulation of cell cycle progression and proliferation, its implication on chromatin remodeling during transcription, replication and DNA repair, the regulation of transcription factors like p53, its implication on DNA-Damage Response, and the regulation of the Cajal Bodies dynamics and nuclear envelope assembly. Furthermore, VRK1 has a role both in the development and in the maintenance of the nervous system. Mutations in the human VRK1 gene are associated to multiple neurodegenerative diseases, like Spinal Muscular Atrophy or Aminotrophic Lateral Sclerosis. In the present work, we have generated and characterized all known VRK1 mutants that have been identified in patients with neurodegenerative diseases ([R89Q], [H119R], [R133C], [G135R], [L195V], [V236M], [R321C], [R358X]). We determined the effect of the mutations on VRK1 stability and its autophosphorylation and transphosphorylation of its known substrates, such as p53, histone H3, 53BP1, NBS1 and coilin. VRK1 is a very stable protein. Some mutants have a significantly reduced half-life. Regarding to the kinase activity, some mutants have a reduced autophosphorylation but they maintain the phosphorylation of its targets. Others have altered the auto-phosphorylation and the substrate-specific phosphorylation activity. We conclude that the functional alteration of the VRK1 mutations and the impairment of its function contribute to the pathogenesis of the neurodegenerative phenotypes observed in patient