Epigenetics of Neurodegenerative Diseases

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two serious neurodegenerative diseases. A rare form of familial ALS is caused by mutations in the FUS gene that lead to a change in the nuclear localization sequence and to cytoplasmic FUS aggregation. FUS aggregation is also found in a sub-form of sporadic FTD (FTLD-FUS), and both are grouped together as FUS-opathies. The pathological picture suggests a direct connection between degeneration and cellular redistribution of FUS, either through loss of normal core functions or toxic functions of FUS in the cytoplasm, or a combination of both. FUS binds to RNA, DNA and numerous other proteins and has multiple functions. It plays a role as a transcription regulator and interacts with transcription factors, proteins in the transcription machinery and proteins involved in mRNA splicing. Binding to epigenetic regulators could also indirectly modify transcription. The incorrect localization of FUS in FUS-opathies can thus also induce the cellular distribution of one or more of these proteins, changing the homeostasis of histone modifications and ultimately gene expression. Preliminary in vitro studies are indicative of a connection between chromatin modifications and FUS, however the complexity of possible modifications of the chromatin structure by FUS in the CNS as well as their consequences and pathomechanical relevance for the diseases have not been investigated so far. The aim of this collaborative project is to elucidate the connection between FUS, FUS mutations and epigenetic chromatin modifications in vivo and to correlate these data with corresponding transcriptome changes, phenotypes in transgenic mice and FUS-opathies. Our working hypothesis is that the redistribution of FUS from the cell nucleus into the cytoplasm modifies the chromatin remodeling dynamics and the associated epigenomic signatures. This in turn leads to impairments of genetic programs that are relevant for cognitive functions and neurological deficits. The analysis of a unique collection of available FUS mouse models for genome-wide and cell type-specific chromatin and transcriptome changes using next-generation sequencing will provide detailed insight into the role of nuclear, cytoplasmic and mutant FUS in regulating chromatin composition, downstream effects and their pathogenetic significance. The identification of a disease-specific epigenetic signature would offer a direct route to new therapeutic interventions, since various regulatory molecules for chromatin remodeling enzymes are available.

(Link: https://gepris.dfg.de/gepris/projekt/316482056?language=en)

The PC1 project is carried out as part of the PsyCourse project and aims to identify clinical, neurobiological and molecular genetic signatures of the course of serious mental illnesses. Since the project is based on the clinical research group 241 (KFO 241), the focus is on schizophrenia (SZ) and bipolar disorder (BD). In order to better illustrate the etiological overlap between psychiatric phenotypes, we will now include unipolar depression in our concept. Over the next 3 years, we will build a fully phenotyped cohort of 1,700 patients (700 SZ, 700 BD, 300 MDD) and 500 controls. All of these study participants are intensively phenotyped at at least 4 timepoints (0, 6, 12, 18 months). Biological samples are also taken at all of these timepoints and sent to biobanking (blood, DNA, RNA, plasma, serum). By using the Germany-wide KFO 241 recruitment platform, PC1 from PsyCourse creates a unique resource that is available to the entire consortium for human projects. Using state-of-the-art machine learning methods, we will use the phenotypic information that we collect from study participants at the time of enrollment and during the course of the study to define novel target phenotypes of the trajectory and treatment response for further molecular and statistical analyses. We will also use machine learning approaches to explore an individualized diagnostic classification and prognosis. Extensive data records of various types are included in these analyses, including socidemographic, psychopathological, neurocognitive and genomic data. This step will also allow us to place the individuals on the edges of the distribution, i.e. to identify those with an extremely poor trajectory and those with an extremely good trajectory. Using complete genome sequencing, we will examine these extreme groups for the involvement of rare variants in the expression of these special progression phenotypes. PC1 will also use a novel microRNAoma sequencing approach to investigate the extent to which regulatory elements can be used as novel biomarkers for the course of the SC. With the approaches mentioned above, PC1 represents a core project within PsyCourse, which on the one hand creates the basis for clinical-scientific analyses and on the other hand defines new course phenotypes on the basis of the data collected, which are directly incorporated into the molecular analyses of PC1 and other PsyCourse Projects.

(Link: https://gepris.dfg.de/gepris/projekt/268615304?language=en)

The Priority Program aims at identifying the functionally relevant ncRNA-target interactions, the underlying molecular mechanisms of regulation and the causal links to major neurological diseases. The focus will be on recently “emerging” non-coding RNAs with a documented gene regulatory function (miRNAs, endo-siRNA, piRNAs, lincRNAs). To address ncRNA function and regulation as a function of the spatiotemporal context, investigations will be performed at various stages of nervous system development to adulthood. Various complexity levels will be considered, from molecular machineries via individual cells to the circuit level. The inclusion of different model organisms in the program will therefore allow us to obtain insights into the conservation and evolution of ncRNA mechanisms. Mechanistic projects will focus on action of ncRNAs and their role on transcriptional and/or post-transcriptional regulatory mechanisms in the developing and adult nervous system, as well as the interplay of ncRNAs and RNA-binding proteins (RBPs) and its role in the regulation of ncRNA biogenesis and function. Individual projects should bridge several disciplines, i.e. combining functional analysis with state-of-the-art molecular biology (e.g. massive parallel sequencing), biochemical (e.g. RBP-CLIP, quantitative proteomics) and/or bioinformatics/systems biology (e.g. pathway analysis, ncRNA target prediction) approaches. Therefore, collaboration between participating groups of the program is strongly encouraged.