Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice

Souchet, Benoît; Audrain, Mickaël; Billard, J.M.; Dairou, Julien; Fol, Romain; Orefice, Nicola Salvatore; Tada, Satoru; Gu, Yuchen; Dufayet-Chaffaud, Gaelle; Limanton, Emmanuelle; Carreaux, François; Bazureau, Jean Pierre; Alves, Sandro; Meijer, Laurent; Janel, Nathalie; Braudeau, Jérôme; Cartier, Nathalie

doi:10.1186/s40478-019-0678-6

Cited by 34 publications

(39 citation statements)

References 50 publications

(55 reference statements)

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“…S2 and S3 ). Therefore, previously established concentrations for in vivo treatments of Dyrk1A hyperactivity in Drosophila and mouse were used ( 47 , 48 ). PC-RFP and PC-Dyrk1A zebrafish larvae were treated for four consecutive days either with ProINDY (2.5 μM) or Leucettine L41 (2 μM) starting at 3 dpf when PCs begin to differentiate and express hDyrk1A ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A novel inhibitor rescues cerebellar defects in a zebrafish model of Down syndrome–associated kinase Dyrk1A overexpression

Buchberger

Schepergerdes

Flaßhoff

et al. 2021

Journal of Biological Chemistry

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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.

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Section: Resultsmentioning

confidence: 99%

A novel inhibitor rescues cerebellar defects in a zebrafish model of Down syndrome–associated kinase Dyrk1A overexpression

Buchberger

Schepergerdes

Flaßhoff

et al. 2021

Journal of Biological Chemistry

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“…DYRK1A inhibition has been proposed as a putative therapeutic strategy in AD, since it reduces APP phosphorylation and has a positive impact on restoring abnormal phenotypes in AD mouse models 7 30 61 62 63 . To study the interaction of DYRK1A and APP we cultured human differentiated neurons to analyze the axonal transport properties of fluorescently labeled APP vesicles after DYRK1A modulation.…”

Section: Discussionmentioning

confidence: 99%

DYRK1A role in microtubule-based axonal transport regulates the retrograde dynamics of APP vesicles in human neurons

Bessone

Karmirian

Goto-Silva

et al. 2021

Preprint

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In Alzheimer ́s Disease (AD) the abnormal intracellular distribution of the amyloid precursor protein (APP) affects its processing and, consequently, the generation of Aβ. Axonal transport plays key roles in the neuronal distribution of APP. The dual-specificity- tyrosine phosphorylation-regulated-kinase-1A (DYRK1A) has been associated with AD onset since its overexpression was found in Down syndrome and sporadic AD patients. Experimental evidence confirmed that APP and tau phosphorylations are mediated by DYRK1A. Moreover, DYRK1A can regulate the cytoskeletal architecture by phosphorylation of both tubulin subunits and microtubule-associated proteins. Therefore, we tested whether DYRK1A has a role in APP axonal transport regulation. We developed highly-polarized human-derived neurons in 2D cultures. At day 14 after terminal plating we inhibited DYRK1A for 48hs with harmine (7.5 μM). DYRK1A overexpression was induced to perform live-cell imaging of APP-loaded vesicles in axons and analyzed transport dynamics. A custom-made MATLAB routine was developed to track and analyze single particle dynamics. Short-term harmine treatment reduced axonal APP vesicles density, due to a reduction in retrograde particles. Contrarily, DYRK1A overexpression enhanced axonal APP density, due to an increase in the retrograde and stationary component. Moreover, both harmine-mediated DYRK1A inhibition and DYRK1A overexpression revealed opposite phenotypes on single particle dynamics, affecting primarily dynein processivity. These results revealed an increased retrieval of distal APP vesicles in axons when DYRK1A is overexpressed and reinforce the suggestion that DYRK1A enhance APP endocytosis. Taken together our results suggest that DYRK1A has a relevant role in the regulation of axonal transport and sub-cellular positioning of APP vesicles. Therefore, our work shed light on the role of DYRK1A in axonal transport regulation, and the putative use of harmine to restore axonal transport impairments.

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“…DYRK1A contains a PEST sequence, a signal peptide for protein degradation via calpain (101, 102). Recently, Souchet et al found that this DYRK1A cleavage is a consequence of the amyloid pathology (103). Resulting truncated forms accumulate in astrocytes and exhibit increased affinity toward a regulator of inflammatory process (103).…”

Section: Statement Of Hypothesis: Plasma Levels Of Dyrk1a Bdnf and mentioning

confidence: 99%

“…Recently, Souchet et al found that this DYRK1A cleavage is a consequence of the amyloid pathology (103). Resulting truncated forms accumulate in astrocytes and exhibit increased affinity toward a regulator of inflammatory process (103). Here, we analyzed these different forms by the use of two different antibodies, one recognizing the full-length form, and the other the full-length and truncated forms of Dyrk1A (Figure 2A) in plasma of control Wistar (WT) and GK rats.…”

Section: Statement Of Hypothesis: Plasma Levels Of Dyrk1a Bdnf and mentioning

confidence: 99%

Hypothesis and Theory: Circulating Alzheimer's-Related Biomarkers in Type 2 Diabetes. Insight From the Goto-Kakizaki Rat

et al. 2019

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Epidemiological data suggest an increased risk of developing Alzheimer's disease (AD) in individuals with type 2 diabetes (T2D). AD is anatomically associated with an early progressive accumulation of Aβ leading to a gradual Tau hyperphosphorylation, which constitute the main characteristics of damaged brain in AD. Apart from these processes, mounting evidence suggests that specific features of diabetes, namely impaired glucose metabolism and insulin signaling in the brain, play a key role in AD. Moreover, several studies report a potential role of Aβ and Tau in peripheral tissues such as pancreatic β cells. Thus, it appears that several biological pathways associated with diabetes overlap with AD. The link between peripheral insulin resistance and brain insulin resistance with concomitant cognitive impairment may also potentially be mediated by a liver/pancreatic/brain axis, through the excessive trafficking of neurotoxic molecules across the blood-brain barrier. Insulin resistance incites inflammation and pro-inflammatory cytokine activation modulates the homocysteine cycle in T2D patients. Elevated plasma homocysteine level is a risk factor for AD pathology and is also closely associated with metabolic syndrome. We previously demonstrated a strong association between homocysteine metabolism and insulin via cystathionine beta synthase (CBS) activity, the enzyme implicated in the first step of the trans-sulfuration pathway, in Goto-Kakizaki (GK) rats, a spontaneous model of T2D, with close similarities with human T2D. CBS activity is also correlated with DYRK1A, a serine/threonine kinase regulating brain-derived neurotrophic factor (BDNF) levels, and Tau phosphorylation, which are implicated in a wide range of disease such as T2D and AD. We hypothesized that DYRK1A, BDNF, and Tau, could be among molecular factors linking T2D to AD. In this focused review, we briefly examine the main mechanisms linking AD to T2D and provide the first evidence that certain circulating AD biomarkers are found in diabetic GK rats. We propose that the spontaneous model of T2D in GK rat could be a suitable model to investigate molecular mechanisms linking T2D to AD.

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Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice

Cited by 34 publications

References 50 publications

A novel inhibitor rescues cerebellar defects in a zebrafish model of Down syndrome–associated kinase Dyrk1A overexpression

A novel inhibitor rescues cerebellar defects in a zebrafish model of Down syndrome–associated kinase Dyrk1A overexpression

DYRK1A role in microtubule-based axonal transport regulates the retrograde dynamics of APP vesicles in human neurons

Hypothesis and Theory: Circulating Alzheimer's-Related Biomarkers in Type 2 Diabetes. Insight From the Goto-Kakizaki Rat

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