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Review
, 278 (2), 236-45

The Role of DYRK1A in Neurodegenerative Diseases

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Review

The Role of DYRK1A in Neurodegenerative Diseases

Jerzy Wegiel et al. FEBS J.

Abstract

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.

Conflict of interest statement

Authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
DYRK1A distribution in DS. DYRK1A immunolabelling with mAb 7F3 in the hippocampus of a 56-year-old DS subject illustrates sector- and layer-specific differences in the distribution of DYRK1A in neurons and neuronal processes in CA1-4 and the dentate gyrus (DG) (a). The most intensive reaction is observed in CA1 pyramidal neurons in bodies and apical dendrites (b, c). High magnification of neuron shows immunoreactivity in the nucleus, cytoplasm and synapses in the CA4 sector (d). Immunoreactivity in cortex is weaker than in hippocampus and is more prominent in pyramidal than granule neurons (e, f). In DS, regionally astrocytes show strong diffuse cell body immunoreactivity (temporal lobe; g). DYRK1A immunoreactivity in the corpora amylacea in the dentate gyrus (h) reflects DYRK1A contribution to astrocytes and neuronal degeneration.
Fig. 2
Fig. 2
Prevalence of 3R tau-positive NFTs in DS. The several-fold more DYRK1A-positive NFTs in DS (a) than in AD (b), and the several-fold more 3R tau–positive NFTs in DS (c) than in AD (d) are direct evidence of the enhanced contribution of DYRK1A to neurofibrillary degeneration in DS. The figure illustrates changes in sector CA1 of a 54-year-old DS male (a and c) and an 84-year-old male (b and d), both diagnosed with severe AD.
Fig. 3
Fig. 3
Contribution of overexpressed DYRK1A to β-amyloidosis and neurofibrillary degeneration in DS. Gene-dose elevation of DYRK1A expression associated with trisomy 21 could lead to the activation of two pathways contributing to neurofibrillary degeneration and one contributing to brain β-amyloidosis. DYRK1A phosphorylates tau at 11 sites, including Thr212; primes tau phosphorylation by GSK-3β; promotes tau aggregation into NFTs and the several-fold increase in the number of DYRK1A-positive NFTs. Phosphorylation of ASF by nuclear DYRK1A increases the level of 3R tau, leading to an imbalance in the 3R/4R-tau ratio and triggering neurofibrillary degeneration with a several-fold increase of 3R-tau–positive NFTs. Both cytoplasmic and nuclear pathways contribute to neurofibrillary degeneration, loss of neuron function, and neuronal death. DYRK1A phosphorylates APP at Thr688 and enhances APP amyloidogenic cleavage, resulting in increased level of Aβ40/42, formation of toxic Aβ oligomers and deposition of fibrillar amyloid in plaques. Brain amyloidosis contributes to loss of neuronal function and possibly also to neuronal loss. Moreover, elevated levels of Aβ may up-regulate DYRK1A expression and enhance the contribution of overexpressed DYRK1A to neurofibrillary degeneration and β-amyloidosis.

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