BDNF and DYRK1A Are Variable and Inversely Correlated in Lymphoblastoid Cell Lines from Down Syndrome Patients

Tlili, Asma; Hoischen, Alexander; Ripoll, Clémentine; Benabou, Eva; Badel, Anne; Ronan, Anne; Touraine, Renaud; Grattau, Yann; Stora, Samantha; Bon, Bregje W.M. van; Vries, Bert de; Menten, Björn; Bockaert, Nele; Gécz, Jozef; Antonarakis, Stylianos E.; Campion, Dominique; Potier, Marie‐Claude; Delabar, Jean–Maurice; Janel, Nathalie

doi:10.1007/s12035-012-8284-7

Cited by 15 publications

(20 citation statements)

References 26 publications

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“…Other reports have shown increased expression of cFOS and EGR1 in response to oxidative stress (45,46) and suggested that this induction is protective (47). If elevated levels of IEG proteins in Tc1 mice are a protective response to elevated levels of oxidative stress, they may be a compensatory response in Tc1 (and DS) and not an abnormality that would be beneficial to alter directly with pharmacotherapies.In contrast to observations in human DS lymphoblastoid cell lines (48), no correlations were observed in Tc1 brain regions between the levels of DYRK1A and BDNF. Indeed, BDNF levels were decreased and only in Tc1 cortex.…”

Section: Discussionmentioning

confidence: 70%

Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain

Ahmed¹,

Dhanasekaran²,

Tong

et al. 2013

Human Molecular Genetics

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Tc1 mouse model of Down syndrome (DS) is functionally trisomic for ∼120 human chromosome 21 (HSA21) classical protein-coding genes. Tc1 mice display features relevant to the DS phenotype, including abnormalities in learning and memory and synaptic plasticity. To determine the molecular basis for the phenotypic features, the levels of 90 phosphorylation-specific and phosphorylation-independent proteins were measured by Reverse Phase Protein Arrays in hippocampus and cortex, and 64 in cerebellum, of Tc1 mice and littermate controls. Abnormal levels of proteins involved in MAP kinase, mTOR, GSK3B and neuregulin signaling were identified in trisomic mice. In addition, altered correlations among the levels of N-methyl-D-aspartate (NMDA) receptor subunits and the HSA21 proteins amyloid beta (A4) precursor protein (APP) and TIAM1, and between immediate early gene (IEG) proteins and the HSA21 protein superoxide dismutase-1 (SOD1) were found in the hippocampus of Tc1 mice, suggesting altered stoichiometry among these sets of functionally interacting proteins. Protein abnormalities in Tc1 mice were compared with the results of a similar analysis of Ts65Dn mice, a DS mouse model that is trisomic for orthologs of 50 genes trisomic in the Tc1 plus an additional 38 HSA21 orthologs. While there are similarities, abnormalities unique to the Tc1 include increased levels of the S100B calcium-binding protein, mTOR proteins RAPTOR and P70S6, the AMP-kinase catalytic subunit AMPKA, the IEG proteins FBJ murine osteosarcoma viral oncogene homolog (CFOS) and activity-regulated cytoskeleton-associated protein (ARC), and the neuregulin 1 receptor ERBB4. These data identify novel perturbations, relevant to neurological function and to some seen in Alzheimer's disease, that may occur in the DS brain, potentially contributing to phenotypic features and influencing drug responses.

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Section: Discussionmentioning

confidence: 70%

Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain

Ahmed¹,

Dhanasekaran²,

Tong

et al. 2013

Human Molecular Genetics

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“…These immortalized cells, which are grown in cell culture medium, have no direct relations with the tissues or cells producing DYRK1A in plasma. Although it is too early to differentiate between a genetic or epigenetic mechanism, these results together with the observation that DYRK1A levels vary among the population, 12 suggest that DYRK1A decrease might be a novel risk factor for AD.…”

Section: Discussionmentioning

confidence: 93%

“…11,12 Proteins separated by SDS–PAGE were transferred to a nitrocellulose membrane (ProtanR) using a slot blot apparatus (Proteigene, St Marcel, France). Membranes were saturated by incubation in 5% w/v nonfat milk powder in Tris–saline buffer (1.5 m M Tris base, pH 8; 5 m M NaCl; 0.1% Tween-20) and incubated overnight at 4 °C with antibodies against DYRK1A (1/250; Abnova Corporation, Taipei, Taiwan; H00001859-M01).…”

Section: Methodsmentioning

confidence: 99%

Plasma DYRK1A as a novel risk factor for Alzheimer’s disease

et al. 2014

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To determine whether apparent involvement of DYRK1A in Alzheimer's disease (AD) pathology makes it a candidate plasma biomarker for diagnosis, we developed a method to quantify plasma DYRK1A by immunoblot in transgenic mouse models having different gene dosages of Dyrk1a, and, consequently, different relative protein expression. Then, we measured plasma DYRK1A levels in 26 patients with biologically confirmed AD and 25 controls (negative amyloid imaging available on 13). DYRK1A was detected in transgenic mouse brain and plasma samples, and relative levels of DYRK1A correlated with the gene copy number. In plasma from AD patients, DYRK1A levels were significantly lower compared with controls (P<0.0001). Results were similar when we compared AD patients with the subgroup of controls confirmed by negative amyloid imaging. In a subgroup of patients with early AD (CDR=0.5), lower DYRK1A expression was confirmed. In contrast, no difference was found in levels of DYRK1B, the closest relative of DYRK1A, between AD patients and controls. Further, AD patients exhibited a positive correlation between plasma DYRK1A levels and cerebrospinal fluid tau and phosphorylated-tau proteins, but no correlation with amyloid-β42 levels and Pittsburgh compound B cortical binding. DYRK1A levels detected in lymphoblastoid cell lines from AD patients were also lower when compared with cells from age-matched controls. These findings suggest that reduced DYRK1A expression might be a novel plasma risk factor for AD.

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“…XBP1s has also been shown to regulate the expression of ADAM10, an α-secretase that cleaves β-amyloid and generates non-toxic species [67]. These reports suggest that XBP1s overexpression observed in DS models might be an attempt of DS cells to either protect themselves against toxic β-amyloid species produced as a result of APP overexpression [68], or as a protection against the lack of neurotrophic factors, also observed in DS models [69, 70]. A similar induction of UPR has also been observed in cataracts [71], epilepsy [72], hypothyroidism [73] and diabetes [74].…”

Section: Discussionmentioning

confidence: 99%

The burden of trisomy 21 disrupts the proteostasis network in Down syndrome

et al. 2017

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Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21. Abnormalities in chromosome number have the potential to lead to disruption of the proteostasis network (PN) and accumulation of misfolded proteins. DS individuals suffer from several comorbidities, and we hypothesized that disruption of proteostasis could contribute to the observed pathology and decreased cell viability in DS. Our results confirm the presence of a disrupted PN in DS, as several of its elements, including the unfolded protein response, chaperone system, and proteasomal degradation exhibited significant alterations compared to euploid controls in both cell and mouse models. Additionally, when cell models were treated with compounds that promote disrupted proteostasis, we observed diminished levels of cell viability in DS compared to controls. Collectively our findings provide a cellular-level characterization of PN dysfunction in DS and an improved understanding of the potential pathogenic mechanisms contributing to disrupted cellular physiology in DS. Lastly, this study highlights the future potential of designing therapeutic strategies that mitigate protein quality control dysfunction.

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BDNF and DYRK1A Are Variable and Inversely Correlated in Lymphoblastoid Cell Lines from Down Syndrome Patients

Cited by 15 publications

References 26 publications

Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain

Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain

Plasma DYRK1A as a novel risk factor for Alzheimer’s disease

The burden of trisomy 21 disrupts the proteostasis network in Down syndrome

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