EpiFUS - Role of FUS in regulating epigenetic modifications: consequences for amyotrophic lateral sclerosis and frontotemporal dementia
Clinical Neurology; Neurosurgery and Neuroradiology
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
The cytoplasmic accumulation of the normally predominantly nuclear located FUS protein is linked to familial forms of amyotrophic lateral sclerosis due to mutations in the FUS gene (ALS-FUS) and a subset of sporadic frontotemporal lobar degeneration (FTLD-FET/FUS), two fatal neurodegenerative diseases. FUS is a DNA/RNA binding protein with in a large number of functions, particularly in all steps of gene expression, including transcription, alternative splicing and mRNA transport. However, the consequences of FUS mutations and the impact of toxic gain of function of the mutation and/or loss of FUS function due to redistribution particularly in the adult central nervous system are only poorly understood due to the fact that constitutional knock-out and knock-in mouse models are embryonic lethal. We therefore generated and characterized two new mouse models to address these questions (i) mice producing an inducible form of mutated FUS in mature neurons and (ii) mice producing an inducible knock-out of FUS in mature neurons. Both mouse lines showed no motor impairment, but a more complex and subtle phenotype indicating impairments of structures involved in sociability, task performance, and motor coordination. Comprehensive transcriptomic analysis revealed changes in the expression of genes associated with synaptic plasticity and memory functions in both mouse lines. While no obvious changes were detected in histone modifications, we identified for the first time severely altered RNA methylation, i.e. hypermethylation particularly of RNAs encoding for synaptic proteins upon nuclear loss of Fus. These data may suggest that loss of FUS function affects the machinery that controls m6A RNA methylation of transcripts that are synaptically transcribed. These results are particularly interesting as m6A methylation of RNAs is associated with an increased aggregation property of RNA-binding proteins via phase separation, a process that is considered to be crucial in the pathogenesis of FUS-opathies. The generated data sets in this proposal are highly valuable tools to further investigate the impact of epigenetic/transcriptomic regulation by FUS that might ultimately offer new avenues towards therapeutic interventions.
Publications
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Review: Neuropathology of non‐tau frontotemporal lobar degeneration. Neuropathology and Applied Neurobiology, 45(1), 19-40.
Neumann, M. & Mackenzie, I. R. A.
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Conserved reduction of m6A RNA modifications during aging and neurodegeneration is linked to changes in synaptic transcripts. Proceedings of the National Academy of Sciences, 120(9).
Castro-Hernández, Ricardo; Berulava, Tea; Metelova, Maria; Epple, Robert; Peña, Centeno Tonatiuh; Richter, Julia; Kaurani, Lalit; Pradhan, Ranjit; Sakib, M. Sadman; Burkhardt, Susanne; Ninov, Momchil; Bohnsack, Katherine E.; Bohnsack, Markus T.; Delalle, Ivana & Fischer, Andre
