Team Rebholz

Signaling mechanisms in neuorolgical disorders


Team leader :  Heike Rebholz

Team member :  Demetra Ballardin  |   Jose Cruz Gamero  |   Marianne Garrido  |   France Renard  |   Renata Santos

 

 

Variants of hundreds of genes have been shown to  lead to  neurodevelopmental and autism spectrum disorder (ASD). Amongst these genes are many kinases, however, their role in the etiology of ASD is not well understood. We study in detail, in mouse models, how mutations in kinase genes affect the phosphorylation of the overall proteome in a cell-specific manner, given that different cell types, in particular different neuronal types, exhibit their own distinct and characteristic  proteome and specific mechanisms that regulate the activities of kinases.

We generated several mouse models of a newly described autism-condition that is linked to mutations in the gene encoding  for a kinase termed CK2. We aim to understand to what degree these models copy the human condition and what the underlying mechanisms are that lead to pathophysiologal alterations. Ultimately, we will test, in our models, if  pharmacological and genetical interventions to rescue the function of the kinase CK2 or its downstream effectors can reverse the phenotypes.  Our work has a clear translational mandate, to  find targets for therapies for OCNDS and for autism patients in general.

We also pursue a research axis to dissect network and biochemical alterations in Parkinson’s disease in a mouse models of Parkinson’s disease and of L-DOPA induced dyskinesia.

 

Confocal images of primary hippocampal neurons, stained with PSD-95 and vGLut1 antibodies.

 

5 main publications

Ballardin D, Cruz-Gamero JM, Bienvenu T, Rebholz H. Comparing Two Neurodevelopmental Disorders Linked to CK2: Okur-Chung Neurodevelopmental Syndrome and Poirier-Bienvenu Neurodevelopmental Syndrome-Two Sides of the Same Coin?. Front Mol Biosci. 2022;9:850559. doi: 10.3389/fmolb.2022.850559. eCollection 2022. Review.

Dominguez I, Cruz-Gamero JM, Corasolla V, Dacher N, Rangasamy S, Urbani A, Narayanan V, Rebholz H. Okur-Chung neurodevelopmental syndrome-linked CK2α variants have reduced kinase activity. Hum Genet. 2021 May 4;. doi: 10.1007/s00439-021-02280-5.

Santos R, Linker SB, Stern S, Mendes APD, Shokhirev MN, Erikson G, Randolph-Moore L, Racha V, Kim Y, Kelsoe JR, Bang AG, Alda M, Marchetto MC, Gage FH. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Mol Psychiatry. 2021 Jun;26(6):2440-2456. doi: 10.1038/s41380-020-00981-3. Epub 2021 Jan 4.

Castello J, Cortés M, Malave L, Kottmann A, Sibley DR, Friedman E, Rebholz H.  The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia. Sci Rep. 2020 Feb 13;10(1):2542. doi: 10.1038/s41598-020-59011-5. PubMed PMID: 32054879; PubMed Central PMCID: PMC7018760.

Castello J, LeFrancois B, Flajolet M, Greengard P, Friedman E, Rebholz H. CK2 regulates 5-HT4 receptor signaling and modulates depressive-like behavior. Mol Psychiatry. 2018 Apr;23(4):872-882. doi: 10.1038/mp.2017.240.

Picture of the lab