DYRK1A
Dual specificity tyrosine-phosphorylation-regulated kinase 1A (EC 2.7.12.1) (Dual specificity YAK1-related kinase) (HP86) (Protein kinase minibrain homolog) (MNBH) (hMNB) [DYRK] [MNB] [MNBH]
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An effective therapy has not yet been developed for Alzheimer's disease (AD), in part because pathological changes occur years before clinical symptoms manifest. We recently showed that decreased plasma DYRK1A identifies individuals with mild cognitive impairment (MCI) or AD, and that aged mice have higher DYRK1A levels. We assessed DYRK1A in plasma in young/aged controls and in elderly cognitive complainers with low (L) and high (H) brain amyloid load. DYRK1A level increases with age in humans. However, plasma from elderly individuals reporting cognitive complaints showed that the H group had the same DYRK1A level as young adults, suggesting that the age-associated DYRK1A increase is blocked in this group. L and H groups had similar levels of clusterin. These results are reflective of early changes in the brain. These observations suggest that plasma DYRK1A and not clusterin could be used to classify elderly memory complainers for risk for amyloid beta pathology.
Keywords
- Alzheimer's disease
- aging
- blood marker
- immunometric test
The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.
MeSH Terms
- Alzheimer Disease
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Animals
- Brain
- Cholinergic Neurons
- Disease Models, Animal
- Down Syndrome
- Gene Dosage
- Male
- Mice, 129 Strain
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Mice, Transgenic
- Nerve Degeneration
- Peptide Fragments
- Phenotype
- Phosphorylation
- Protein-Serine-Threonine Kinases
- Protein-Tyrosine Kinases
- tau Proteins
Keywords
- APP
- Down syndrome
- Dyrk1A
- Neurodegeneration
- Senescence
- Tau
- Ts65Dn
In [i]Caenorhabditis elegans[/i], reduction of insulin/IGF-1 like signaling and loss of germline stem cells both increase lifespan by activating the conserved transcription factor DAF-16 (FOXO). While the mechanisms that regulate DAF-16 nuclear localization in response to insulin/IGF-1 like signaling are well characterized, the molecular pathways that act in parallel to regulate DAF-16 transcriptional activity, and the pathways that couple DAF-16 activity to germline status, are not fully understood at present. Here, we report that inactivation of MBK-1, the [i]C. elegans[/i] ortholog of the human FOXO1-kinase DYRK1A substantially shortens the prolonged lifespan of [i]daf-2[/i] and [i]glp-1[/i] mutant animals while decreasing wild-type lifespan to a lesser extent. On the other hand, lifespan-reduction by mutation of the MBK-1-related kinase HPK-1 was not preferential for long-lived mutants. Interestingly, [i]mbk-1[/i] loss still allowed for DAF-16 nuclear accumulation but reduced expression of certain DAF-16 target genes in germline-less, but not in [i]daf-2[/i] mutant animals. These findings indicate that [i]mbk-1[/i] and [i]daf-16[/i] functionally interact in the germline- but not in the [i]daf-2[/i] pathway. Together, our data suggest [i]mbk-1[/i] as a novel regulator of [i]C. elegans[/i] longevity upon both, germline ablation and DAF-2 inhibition, and provide evidence for [i]mbk-1[/i] regulating DAF-16 activity in germline-deficient animals.
MeSH Terms
- Animals
- Animals, Genetically Modified
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Forkhead Transcription Factors
- Gene Expression Regulation
- Genotype
- Longevity
- Mutation
- Phenotype
- Phosphorylation
- Protein-Serine-Threonine Kinases
- Protein-Tyrosine Kinases
- Receptor, Insulin
- Receptors, Notch
- Time Factors
Keywords
- DYRK1
- FOXO
- aging
- phosphorylation
- signaling
Down syndrome (DS) or Trisomy 21 causes intellectual disabilities in humans and the Ts65Dn DS mouse model is deficient in learning and memory tasks. DYRK1A is triplicated in DS and Ts65Dn mice. Ts65Dn mice were given up to ~20mg/kg/day epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, or water beginning on postnatal day 24 and continuing for three or seven weeks, and were tested on a series of behavioral and learning tasks, including a novel balance beam test. Ts65Dn as compared to control mice exhibited higher locomotor activity, impaired novel object recognition, impaired balance beam and decreased spatial learning and memory. Neither EGCG treatment improved performance of the Ts65Dn mice on these tasks. Ts65Dn mice had a non-significant increase in Dyrk1a activity in the hippocampus and cerebellum. Given the translational value of the Ts65Dn mouse model, further studies will be needed to identify the EGCG doses (and mechanisms) that may improve cognitive function.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- Brain Chemistry
- Catechin
- Cognition Disorders
- Down Syndrome
- Female
- Growth
- Learning
- Maze Learning
- Mice
- Mice, Transgenic
- Protein-Serine-Threonine Kinases
- Protein-Tyrosine Kinases
- Recognition, Psychology
Keywords
- Cognition
- Down syndrome
- Mouse model
- Treatment
- Trisomy 21