The RTG will explore the complex interplay between neurodevelopment/-developmental disorders and adult-onset neuropsychiatric and neurodegenerative diseases. Projects address the following key questions:
Research area 1: How do disease genes impact on neurodevelopment?
Research area 2: How do neurodevelopmental factors influence vulnerability to disease-precipitating insults?
Research area 3: What are the commonalities in genetics and pathophysiological pathways between neurodevelopmental and neuropsychiatric / -degenerative diseases?
The RTG will investigate these questions from the molecular to the behavioral level in animal models, hiPSC-based cellular model systems and patient-specific biomaterials using state-of-the-art technologies in human genetics, genome-editing, imaging, animal behavior, electrophysiology, pharmacology, developmental and molecular biology, and biochemistry.
Myelination of axons is essential to ensure neuronal communication and neural circuit function. Abnormalities in myelination are a common pathological hallmark of a number of CNS disorders including leukodystrophies, multiple sclerosis, subsets of autism spectral disorders, synucleinopathies, amyotrophic lateral sclerosis and schizophrenia. Myelin maintenance during adulthood is significantly supported through the continuous production of myelin by existing oligodendrocytes. The underlying molecular mechanisms, however, are only poorly understood.
The goal of this project is to investigate the function of Sox10 and Sox8 in myelin maintenance. These transcription factors represent interesting candidate regulators of myelin homeostasis because of their role during developmental myelination, their continued expression in mature oligodendrocytes and their implication as genetic vulnerability factors for multiple sclerosis and schizophrenia. To this end, stage-specific conditional compound mouse mutants will be generated and analyzed using a combination of histological, molecular and behavioral methods. Special emphasis will be placed on issues of redundancy and uniqueness of the two transcription factors.
Our study will shed light on the regulatory requirements of myelin maintenance and potential causes of hypomyelinating and oligodendrocyte-induced demyelinating conditions and thereby connect developmental to adult-onset disease in humans.
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system with a complex and as of yet incompletely understood pathophysiology. About one third of the risk for the disease is conferred via genetic factors. While a vast array of these genetic approaches revealed factors associated with cellular or humoral immune responses towards myelin, only few studies addressed mechanisms directly responsible for CNS tissue susceptibility towards the autoimmune attack so far. In this context, we have previously shown that the neurotrophic growth factors ciliary neurotrophic factor and leukemia inhibitory factor play a major role for the protection of oligodendrocytes and myelin in an inflammatory environment.
Beyond that, genetic regulators of oligodendrogenesis and myelination represent interesting candidate factors to modulate CNS susceptibility during autoimmune demyelination. Here, transcription factors of the SoxE protein family with developmentally regulated oligodendrocytic expression are of particular interest. In humans, single nucleotide polymorphisms in the SOX8 gene have been associated with susceptibility towards MS.
Our analyses employ different genetic models with deficiency for distinct SoxE protein family members and comprise
i) behavioral studies in the EAE and cuprizone models of experimental demyelination,
ii) histopathological and ultrastructural analyses to quantify the extent of demyelination, inflammation and axonal injury as well as analyses of oligodendroglial precursor activity,
iii) organotypic cerebellar slices after lysolecithine induced demyelination as an in vitro model system.
In the next step, we aim to gain insight into the molecular targets and programs of SoxE protein family members in response to a demyelinating challenge and also analyze tissue from MS patients using qRT-PCR, in-situ hybridization, and immunohistochemistry. These studies are expected to improve our understanding on developmental mechanisms of myelin protection and repair in MS, thus promoting the development of new restorative treatment strategies.
Multiple system atrophy (MSA) is an atypical parkinsonian disorder with a rapidly progressing clinical course. Myelin loss and neurodegeneration are major and widespread neuropathological hallmarks. These degenerative processes are associated with the accumulation of alpha-synuclein within oligodendrocytes, the myelin-forming cells of the central nervous system, characterizing MSA as synucleinopathy and primary oligodendrogliopathy. Yet, exact pathomechanisms linked to oligodendroglial alpha-synuclein accumulation are poorly understood, which may partly explain the lack of efficient therapies for MSA.
The goal of this project is to investigate functional consequences of alpha-synuclein pathology in oligodendrocytes with particular focus on effects on myelin homeostasis. Molecular targets that are dysregulated by alpha-synuclein accumulation have been identified by RNA sequencing of alpha-synuclein-overexpressing primary oligodendrocytes and include key proteins of several neurodevelopmental pathways such as the Notch- and Wnt-signaling pathway required for myelin maintenance. Candidate pathways will be validated in human MSA post-mortem tissue and examined as well as modified in pre-clinical MSA models.
Our study will shed light into molecular mechanisms underlying myelin loss and neurodegeneration in MSA, thereby possibly defining novel targets for interventional strategies in MSA.
A large number of neurodevelopmental, -psychiatric, and -degenerative disorders share abnormalities in synapse development and homeostasis as pathophysiological pathway and vulnerability factor . A hallmark of Retinitis pigmentosa, a group of hereditary retinal degenerative diseases, is the primary loss of the rod photoreceptors followed by the secondary loss of the cone photoreceptors. The cell biological and molecular basis for the propagation of cell death from degenerating rod to healthy cone photoreceptors is unknown. Various mechanisms may contribute, possibly involving also synaptic pathways and proteins. Indeed, differential sensitivity to degeneration is observed in mice deficient for the presynaptic protein Bassoon (Bsn). Despite the fact that the synaptopathogenic effect of the Bsn-deficiency affects both photoreceptor types equally, only cone photoreceptors undergo late onset degeneration. In our project we will use the Bsn-deficient mouse as a model to investigate the cause of differential vulnerability of retinal photoreceptors to a synaptopathy.
Moreover, our project is of central conceptual importance to the RTG, as it provides a core method (electron microscopy) from which a number of projects in the RTG will benefit.
Mutations in the Spastic Paraplegia Gene11 (SPG11), encoding spatacsin, cause the most frequent form of complicated autosomal recessive (AR) hereditary spastic paraplegia (HSP) and juvenile onset amyotrophic lateral sclerosis (ALS5). The gene SPG11, encoding spatacsin is a prominent example for multisystem neurodegeneration. We recently found indications for a neurodevelopmental phenotype.
The project aims to identify the pathophysiological processes caused by SPG11 mutations in neurodevelopment and degeneration. To this end, neural progenitor cells and neurons derived from SPG11 patients‘ induced pluripotent stem cells will be analyzed for understanding disease relevant mechanisms, using histological, biochemical, pharmacological, and live-cell imaging approaches and electrophysiology.
Results from this project are expected to significantly further our understanding of the temporal susceptibility of spatacsin in distinct neural systems.
Through its production of ceramide, acid sphingomyelinase (ASM) impacts on fundamental processes of neuronal development and plasticity. Transgenic mice with elevated ASM activity display a depression/anxiety phenotype and reduced neurogenesis in the hippocampus. Notably, their behavioral and morphological phenotype can be ameliorated by functional inhibitors of ASM such as the antidepressant fluoxetine.
This project will examine how clinically relevant environmental risk factors for psychiatric disorders impede hippocampal development and function and to which extent perturbation of the ASM/ceramide pathway contributes to different pathological phenotypes. Embedded in a comprehensive and interdisciplinary environment, the experimental mainstay will be the detailed analysis of ASM-deficient and ASM-overexpressing mice subjected to different combinations of early life stressors and pharmacological treatments employing a broad array of behavioral and ex vivo neurophysiologic paradigms.
The classical transient receptor potential channel TRPC6 is an important regulator of neuronal morphogenesis, synaptogenesis, axon pathfinding, and neuronal survival in CNS development that continues to modulate synaptic plasticity into adulthood. Aberrant TRPC6 activity is a shared hallmark of a wider range of neurodevelopmental and
adult‐onset CNS disorders: Loss‐of‐function mutations in TRPC6 have been linked to autism spectrum disorders, and there is recent evidence that TRPC6 channel dysfunction might be a target for the treatment of neurodegenerative diseases such as Alzheimer diseases or psychiatric diseases such as major depression.
This project aims to investigate pathways regulating neuronal TRPC6 activity with a particular focus on the ASM/ceramide system – a candidate pathway to mediate depression‐ and anxiety‐like behavior and to confer vulnerability for neuropsychiatric disease and to further validate TRPC6 as a molecular target for the treatment of
depression. Collectively, this project will provide evidence for the interplay between two novel targets in depression research, the ASM/ceramide system and TRPC6 channels, and might thereby help to define new targets as well as new chemical compounds for the treatment of major depression.
The role of many genes implicated in intellectual disability (ID) in CNS development and function is still to be determined or characterized; it is, however, suspected that ID gene encoded proteins interact in a limited number of molecular pathways and cellular processes. An increasing number of single genes and pathways, amongst them chromatin remodelling and interaction processes, have been emerging as being involved not only in ID but also in the pathophysiology of a larger spectrum of neuropsychiatric disorders, such as autism and schizophrenia.
The role of this project is to characterize the function of chromatin interacting proteins such as CTCF and SETDB1 in neuronal development and function. By studying their function we expect to gain better insight of how their altered function by mutations can result in behavioral and cognitive phenotypes during child- and adulthood. Further patients will be identified and genotype-phenotype correlations will be established. Deregulated pathways will by identified by transcriptome analysis. Furthermore, Drosophila melanogaster will be used as a model organism to investigate the role of chromatin interacting genes/proteins in CNS development and function.
This study will contribute to the identification of molecular pathways and cellular processes in the pathogenesis of ID and also, in regard to other projects of the RTG, to shared pathophysiological pathways between ID and other neuropsychiatric disorders such as schizophrenia.
The transcription factor TCF4 sets a prominent example for the concept that neurodevelopmental disorders share common genetic etiology with adult-onset psychiatric disease. TCF4 haploinsufficiency was identified as the underlying cause for Pitt-Hopkins syndrome (PTHS) – a developmental syndrome associated with severe intellectual disability, whereas common variants of TCF4 have been linked to increased risk for schizophrenia.
This project aims to determine the regulatory function of TCF4 in CNS development and plasticity with a particular focus on the hippocampal formation. To this end, stage-specific conditional TCF4 knockout-mice will be generated and will initially be analyzed using a combination of histological, molecular, electrophysiological, and behavioral methods.
Results from this project are expected to significantly further our understanding of the pathophysiological communalities between neurodevelopmental and neuropsychiatric diseases.