The role of DYRK1A in neurodegenerative diseases.

Recent studies indicate that the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene, which is located on chromosome 21q22.2 and is overexpressed in Down syndrome (DS), may play a significant role in developmental brain defects and in early onset neurodegeneration, neuronal loss and dementia in DS. The identification of hundreds of genes deregulated by DYRK1A overexpression and numerous cytosolic, cytoskeletal and nuclear proteins, including transcription factors, phosphorylated by DYRK1A, indicates that DYRK1A overexpression is central for the deregulation of multiple pathways in the developing and aging DS brain, with structural and functional alterations including mental retardation and dementia. DYRK1A overexpression in DS brains may contribute to early onset neurofibrillary degeneration directly through hyperphosphorylation of tau and indirectly through phosphorylation of alternative splicing factor, leading to an imbalance between 3R-tau and 4R-tau. The several-fold increases in the number of DYRK1A-positive and 3R-tau-positive neurofibrillary tangles in DS support this hypothesis. Moreover, the enhanced phosphorylation of amyloid precursor protein by overexpressed DYRK1A facilitates amyloidogenic amyloid precursor protein cleavage elevating Aβ40 and 42 levels, and leading to brain β-amyloidosis. Therefore, inhibiting DYRK1A activity in DS may serve to counteract the phenotypic effects of its overexpression and is a potential method of treatment of developmental defects and the prevention of age-associated neurodegeneration, including Alzheimer-type pathology.