Novel DYRK1A Inhibitor Rescues Learning and Memory Deficits in a Mouse Model of Down Syndrome.
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ABSTRACT:
SUBMITTER: Stensen W
PROVIDER: S-EPMC8617627 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Growing evidence supports the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity [Tg(Dyrk1a), Ts65Dn, Dp1Yey], all expressing an extra copy of Dyrk1a Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three DS models with the pharmacological DYRK1A inhibitor leucettine L41 leads to normalization of DYRK1A activity and corrects the novel object cognitive impairment observed in these models. Brain functional magnetic resonance imaging reveals that this cognitive improvement is paralleled by functional connectivity remodelling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a quantitative phosphoproteomics method, revealing the implication of synaptic (synapsin 1) and cytoskeletal components involved in synaptic response and axonal organization. These results encourage the development of DYRK1A inhibitors as drug candidates to treat cognitive deficits associated with DS and AD.
| S-EPMC6176987 | biostudies-literature
Project description:The highly conserved dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) plays crucial roles during central nervous system development and homeostasis. Furthermore, its hyperactivity is considered responsible for some neurological defects in individuals with Down syndrome. We set out to establish a zebrafish model expressing human Dyrk1A that could be further used to characterize the interaction between Dyrk1A and neurological phenotypes. First, we revealed the prominent expression of dyrk1a homologs in cerebellar neurons in the zebrafish larval and adult brains. Overexpression of human dyrk1a in postmitotic cerebellar Purkinje neurons resulted in a structural misorganization of the Purkinje cells in cerebellar hemispheres and a compaction of this cell population. This impaired Purkinje cell organization was progressive, leading to an age-dependent dispersal of Purkinje neurons throughout the cerebellar molecular layer with larval swim deficits resulting in miscoordination of swimming and reduced exploratory behavior in aged adults. We also found that the structural misorganization of the larval Purkinje cell layer could be rescued by pharmacological treatment with Dyrk1A inhibitors. We further reveal the in vivo efficiency of a novel selective Dyrk1A inhibitor, KuFal194. These findings demonstrate that the zebrafish is a well-suited vertebrate organism to genetically model severe neurological diseases with single cell type specificity. Such models can be used to relate molecular malfunction to cellular deficits, impaired tissue formation, and organismal behavior and can also be used for pharmacological compound testing and validation.
| S-EPMC8239740 | biostudies-literature
Project description:Down Syndrome (DS) results from the trisomy of human chromosome 21 (HSA21). It is still the most frequent intellectual disability, affecting 1 newborn per 700 births. Among candidate genes explaining intellectual disabilities seen in DS patients, the dual specificity tyrosine-phosphorylation regulated kinase 1A, DYRK1A, is located in the DS critical region of chromosome 21. DYRK1A has become a major screening target for the development of selective and potent pharmacological inhibitors. We here investigated the effects of a relatively selective DYRK1A inhibitor, Leucettine 41 (hereafter L41) in three different trisomic mouse models with increasing genetic complexity, Tg(Dyrk1a), Ts65Dn and Dp1Yey. Leucettines are derived from the marine sponge alkaloid Leucettamine B.
2018-10-17 | PXD008419 | Pride
Project description:Huntington's disease (HD) is classically characterized as a movement disorder, however cognitive impairments precede the motor symptoms by ?15 y. Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD. We discovered that Htt and KCC2 interact in the hippocampi of wild-type and R6/2-HD mice, with a decrease in KCC2 expression in the hippocampus of R6/2 and YAC128 mice. The reduced expression of the Cl--extruding cotransporter KCC2 is accompanied by an increase in the Cl--importing cotransporter NKCC1, which together result in excitatory GABA in the hippocampi of HD mice. NKCC1 inhibition by the FDA-approved NKCC1 inhibitor bumetanide abolished the excitatory action of GABA and rescued the performance of R6/2 mice on hippocampal-associated behavioral tests.
| S-EPMC5816181 | biostudies-literature
Project description:Overexpression of Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS-associated phenotypes have been largely unsuccessful. Epigallocatechin-3-gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS-associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue-specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue-specific-sensitive periods when Dyrk1a regulates cellular processes that shape the long-term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes.
| S-EPMC5606891 | biostudies-literature
Project description:A common feature of diverse brain disorders is the alteration of GABA-mediated inhibition because of aberrant, intracellular chloride homeostasis induced by changes in the expression and/or function of chloride transporters. Notably, pharmacological inhibition of the chloride importer NKCC1 is able to rescue brain-related core deficits in animal models of these pathologies and in some human clinical studies. Here, we show that reducing NKCC1 expression by RNA interference in the Ts65Dn mouse model of Down syndrome (DS) restores intracellular chloride concentration, efficacy of gamma-aminobutyric acid (GABA)-mediated inhibition, and neuronal network dynamics in vitro and ex vivo. Importantly, adeno-associated virus (AAV)-mediated, neuron-specific NKCC1 knockdown in vivo rescues cognitive deficits in diverse behavioral tasks in Ts65Dn animals. Our results highlight a mechanistic link between NKCC1 expression and behavioral abnormalities in DS mice and establish a molecular target for new therapeutic approaches, including gene therapy, to treat brain disorders characterized by neuronal chloride imbalance.
| S-EPMC8531145 | biostudies-literature
Project description:Down syndrome (DS) arises from triplication of genes on human chromosome 21 and is associated with anomalies in brain development such as reduced production of neurons and increased generation of astrocytes. Here, we show that differentiation of cortical progenitor cells into astrocytes is promoted by DYRK1A, a Ser/Thr kinase encoded on human chromosome 21. In the Ts1Cje mouse model of DS, increased dosage of DYRK1A augments the propensity of progenitors to differentiate into astrocytes. This tendency is associated with enhanced astrogliogenesis in the developing neocortex. We also find that overexpression of DYRK1A upregulates the activity of the astrogliogenic transcription factor STAT in wild-type progenitors. Ts1Cje progenitors exhibit elevated STAT activity, and depletion of DYRK1A in these cells reverses the deregulation of STAT. In sum, our findings indicate that potentiation of the DYRK1A-STAT pathway in progenitors contributes to aberrant astrogliogenesis in DS.
| S-EPMC4641506 | biostudies-literature
Project description:Trisomy 21 (Ts21) causes alterations in skeletal development resulting in decreased bone mass, shortened stature and weaker bones in individuals with Down syndrome (DS). There is a sexual dimorphism in bone mineral density (BMD) deficits associated with DS with males displaying earlier deficits than females. The relationships between causative trisomic genes, cellular mechanisms, and influence of sex in DS skeletal abnormalities remain unknown. One hypothesis is that the low bone turnover phenotype observed in DS results from attenuated osteoblast function, contributing to impaired trabecular architecture, altered cortical geometry, and decreased mineralization. DYRK1A, found in three copies in humans with DS, Ts65Dn, and Dp1Tyb DS model mice, has been implicated in the development of postnatal skeletal phenotypes associated with DS. Reduced copy number of Dyrk1a to euploid levels from conception in an otherwise trisomic Ts65Dn mice resulted in a rescue of appendicular bone deficits, suggesting DYRK1A contributes to skeletal development and homeostasis. We hypothesized that reduction of Dyrk1a copy number in trisomic osteoblasts would improve cellular function and resultant skeletal structural anomalies in trisomic mice. Female mice with a floxed Dyrk1a gene (Ts65Dn,Dyrk1afl/wt) were mated with male Osx-Cre+ (expressed in osteoblasts beginning around E13.5) mice, resulting in reduced Dyrk1a copy number in mature osteoblasts in Ts65Dn,Dyrk1a+/+/Osx-Cre P42 male and female trisomic and euploid mice, compared with littermate controls. Male and female Ts65Dn,Dyrk1a+/+/+ (3 copies of DYRK1A in osteoblasts) and Ts65Dn,Dyrk1a+/+/Osx-Cre (2 copies of Dyrk1a in osteoblasts) displayed similar defects in both trabecular architecture and cortical geometry, with no improvements with reduced Dyrk1a in osteoblasts. This suggests that trisomic DYRK1A does not affect osteoblast function in a cell-autonomous manner at or before P42. Although male Dp1Tyb and Ts65Dn mice exhibit similar skeletal deficits at P42 in both trabecular and cortical bone compartments between euploid and trisomic mice, female Ts65Dn mice exhibit significant cortical and trabecular deficits at P42, in contrast to an absence of genotype effect in female Dp1Tyb mice in trabecular bone. Taken together, these data suggest skeletal deficits in DS mouse models and are sex and age dependent, and influenced by strain effects, but are not solely caused by the overexpression of Dyrk1a in osteoblasts. Identifying molecular and cellular mechanisms, disrupted by gene dosage imbalance, that are involved in the development of skeletal phenotypes associated with DS could help to design therapies to rescue skeletal deficiencies seen in DS.
| S-EPMC8624983 | biostudies-literature
Project description:Genetic-dissection studies carried out with Down syndrome (DS) murine models point to the critical contribution of Dyrk1A overexpression to the motor abnormalities and cognitive deficits displayed in DS individuals. In the present study we have used a murine model overexpressing Dyrk1A (TgDyrk1A mice) to evaluate whether functional CNS defects could be corrected with an inhibitory RNA against Dyrk1A, delivered by bilateral intrastriatal injections of adeno-associated virus type 2 (AAVshDyrk1A). We report that AAVshDyrk1A efficiently transduced HEK293 cells and primary neuronal cultures, triggering the specific inhibition of Dyrk1A expression. Injecting the vector into the striata of TgDyrk1A mice resulted in a restricted, long-term transduction of the striatum. This gene therapy was found to be devoid of toxicity and succeeded in normalizing Dyrk1A protein levels in TgDyrk1A mice. Importantly, the behavioral studies of the adult TgDyrk1A mice treated showed a reversal of corticostriatal-dependent phenotypes, as revealed by the attenuation of their hyperactive behavior, the restoration of motor-coordination defects, and an improvement in sensorimotor gating. Taken together, the data demonstrate that normalizing Dyrk1A gene expression in the striatum of adult TgDyrk1A mice, by means of AAVshRNA, clearly reverses motor impairment. Furthermore, these results identify Dyrk1A as a potential target for therapy in DS.
| S-EPMC2561933 | biostudies-literature
Project description:The evidence for a protective role of physical activity on the risk and progression of Alzheimer's disease (AD) has been growing in the last years. Here we studied the influence of a prolonged physical and cognitive stimulation on neurodegeneration, with special emphasis on hippocampal neuron loss and associated behavioral impairment in the Tg4-42 mouse model of AD. Tg4-42 mice overexpress A?4-42 without any mutations, and develop an age-dependent hippocampal neuron loss associated with a severe memory decline. We demonstrate that long-term voluntary exercise diminishes CA1 neuron loss and completely rescues spatial memory deficits in different experimental settings. This was accompanied by changes in the gene expression profile of Tg4-42 mice. Deep sequencing analysis revealed an upregulation of chaperones involved in endoplasmatic reticulum protein processing, which might be intimately linked to the beneficial effects seen upon long-term exercise. We believe that we provide evidence for the first time that enhanced physical activity counteracts neuron loss and behavioral deficits in a transgenic AD mouse model. The present findings underscore the relevance of increased physical activity as a potential strategy in the prevention of dementia.
| S-EPMC5070068 | biostudies-literature