Biology subjects

Rebholz, H.

Publications and source records attributed to Rebholz, H..

3 recordsLinked to original sources

bioRxiv2026

A CK2α-G3BP1 signaling axis regulates local translation in developing neurons and is disrupted in OCNDS

Neurodevelopmental disorders are frequently caused by mutations in pleiotropic kinases, yet downstream effectors driving neuronal pathology remain undefined. Here, we identify the G3BP1-dependent stress granule pathway as the dominant effector of casein kinase 2 (CK2) in developing neurons, implying that its dysregulation underlies the neurodevelopmental deficits of Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS-associated CK2 mutations reduce phosphorylation of G3BP1 at serine 149, promoting aberrant phase separation and persistent granules that sequester neuronal mRNAs and suppress local protein synthesis across axonal and dendritic compartments. These phenotypes produce allele-specific deficits in neuronal morphogenesis, synaptic abundance, and network excitability, which are conserved in a knock-in mouse model and in patient-derived iPSC neurons. G3bp1 knockdown rescues translational and morphological phenotypes across all OCNDS alleles, demonstrating that restoring granule homeostasis reverses neuronal pathology. Together, these findings establish OCNDS as a disorder of compartment-specific translational dysregulation driven by impaired CK2-G3BP1 control of RNA granule homeostasis. SummaryOCNDS mutations disrupt CK2-G3BP1 signaling, causing persistent granules and defective neuronal translation and development.

neuroscience↗

bioRxiv2024

Missense mutation in the activation segment of the kinase CK2 models Okur Chung neurodevelopmental disorder and alters the hippocampal glutamatergic synapse

Exome sequencing has enabled the identification of causative genes of monogenic forms of autism, amongst them, in 2016, CSNK2A1, the gene encoding the catalytic subunit of the kinase CK2, linking this kinase to Okur-Chung Neurodevelopmental Syndrome (OCNDS), a newly described neurodevelopmental condition with many symptoms resembling those of autism spectrum disorder. Thus far, no preclinical model of this condition exists. Here we describe a knockin mouse model that harbors the K198R mutation in the activation segment of the kinase. This region is a mutational hotspot, representing one-third of patients. These mice exhibit behavioral phenotypes that mirror patient symptoms. Homozygous knock-in (KI) mice die mid-gestation while heterozygous KI mice are born at half of the expected mendelian ratio and are smaller in weight and size than wildtype littermates. Heterozygous KI mice showed alterations in cognition and memory-assessing paradigms, enhanced stereotypies, altered circadian activity patterns, and nesting behavior. Phosphoproteome analysis from brain tissue revealed alterations in the phosphorylation status of major pre- and postsynaptic proteins of heterozygous KI mice. In congruence, we detect reduced synaptic maturation in hippocampal neurons and attenuated long-term potentiation in the hippocampus of KI mice. Taken together, K198R KI mice exhibit significant face validity, presenting ASD-relevant phenotypes, synaptic deficits and alterations in synaptic plasticity, all of which strongly validate this line as a mouse model of OCNDS.

neuroscience↗

bioRxiv2020

Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Expression of Abnormal Involuntary Movements

L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinsons Disease. The mechanistic underpinnings of LID remain obscure. Here we report that diminshed sonic hedgehog (Shh) signaling in the basal ganglia caused by the degeneration of midbrain dopamine neurons (DANs) facilitates the formation and expression of LID. We demonstrate that augmenting Shh signaling with agonists of the Shh effector Smoothened attenuates LID in mouse and macaque models of PD. Employing conditional genetic loss-of-function approaches, we show that reducing Shh secretion from DANs or Smo activity in cholinergic interneurons (CINs) promotes LID. Conversely, the selective expression of constitutively active Smo (SmoM2) in CINs is sufficient to render the sensitized aphakia model of PD resistant to LID. Furthermore, acute depletion of Shh from DANs through prolonged optogenetic stimulation in otherwise intact mice and in the absence of L-Dopa produces LID-like involuntary movements. These findings indicate that augmenting Shh signaling in the L-Dopa treated brain may be a promising and unexpected novel therapeutic approach for mitigating the dyskinetic side effects of long-term treatment with L-Dopa

neuroscience↗