Abstract
Down syndrome (DS) caused by a trisomy of chromosome 21 (HSA21), is the most common genetic developmental disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment, early onset of Alzheimer’s disease, congenital heart disease, hypotonia, muscle weakness and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. Among the numerous protein coding genes of HSA21, dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) encodes a proline-directed serine/threonine and tyrosine kinase that plays pleiotropic roles in neurodevelopment in both physiological and pathological conditions. Numerous studies point to a crucial role of DYRK1A protein for brain defects in patients with DS. Thus, DYRK1A inhibition has shown benefits in several mouse models of DS, including improvement of cognitive behaviour. Lastly, a recent clinical trial has shown that epigallocatechine gallate (EGCG), a DYRK1A inhibitor, given to young patients with DS improved visual recognition memory, working memory performance and adaptive behaviour.
Highlights
Down syndrome (DS), known as trisomy 21, is caused by an extra copy of chromosome21 (HSA21)
Giving the large body of evidence demonstrating the involvement of dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) in the braindefects in patients with DS, many studies have evaluated the effect of DYRK1A inhibition on the related defects in patients with DS, many studies have evaluated the effect of DYRK1A inhibition on learning and memory capacities of mouse models of DS
We found that reducing DYRK1A activity to near physiological values through pharmacological approaches or through shRNA against DYRK1A improved the number of DS-induced pluripotent stem cells (iPSCs)-derived neuroprogenitor cell (NPC)
Summary
Down syndrome (DS), known as trisomy 21, is caused by an extra copy of chromosome. Brains from individuals with DS show a reduced volume and alterations in the number and/or morphology of neurons in several specific regions including the frontal cortex, the hippocampus and the cerebellum [2]. Bacterial artificial chromosome (BAC) transgenic mice carrying an extra copy of Dyrk1a show alteration in brain size and neuronal density [22] together with neurodevelopmental delays, motor abnormalities, altered synaptic plasticity, learning and memory deficits (Table 1), recapitulating most of the DS phenotype [23,24,25]. Albeit with subtle nuances (Table 1), have been described in studies on different genetically engineered mice including yeast artificial chromosome (YAC) transgenic mice carrying an extra copy of Dyrk1a and in mice with partial trisomy (Table 1) [26,27]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
