title: Super-Resolution Microscopy Reveals Presynaptic Localization of the ALS/FTD Related Protein FUS in Hippocampal Neurons.
abstract: Fused in Sarcoma (FUS) is a multifunctional RNA-/DNA-binding protein, which is involved in the pathogenesis of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A common hallmark of these disorders is the abnormal accumulation of mutated FUS protein in the cytoplasm. Under normal conditions FUS is confined to the nuclear compartment, in neurons, however, additional somatodendritic localization can be observed. In this study, we carefully analyzed the subcellular localization of endogenous FUS at synaptic sites of hippocampal neurons which are among the most affected cell types in FTD with FUS pathology. We could confirm a strong nuclear localization of FUS as well as its prominent and widespread neuronal expression throughout the adult and developing rat brain, particularly in the hippocampus, the cerebellum and the outer layers of the cortex. Intriguingly, FUS was also consistently observed at synaptic sites as detected by neuronal subcellular fractionation as well as by immunolabeling. To define a pre- and/or postsynaptic localization of FUS, we employed super-resolution fluorescence localization microscopy. FUS was found to be localized within the axon terminal in close proximity to the presynaptic vesicle protein Synaptophysin1 and adjacent to the active zone protein Bassoon, but well separated from the postsynaptic protein PSD-95. Having shown the presynaptic localization of FUS in the nervous system, a novel extranuclear role of FUS at neuronal contact sites has to be considered. Since there is growing evidence that local presynaptic translation might also be an important mechanism for plasticity, FUS - like the fragile X mental retardation protein FMRP - might act as one of the presynaptic RNA-binding proteins regulating this machinery. Our observation of presynaptic FUS should foster further investigations to determine its role in neurodegenerative diseases such as ALS and FTD.
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schoen
authors.affiliation: Institute of Biophysics, Ulm University Ulm, Germany.
authors.forename: Jochen M
authors.initials: JM
authors.lastname: Reichel
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University Ulm, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Demestre
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm UniversityUlm, Germany; Department of Neurology, Ulm UniversityUlm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Putz
authors.affiliation: Institute of Biophysics, Ulm University Ulm, Germany.
authors.forename: Dhruva
authors.initials: D
authors.lastname: Deshpande
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Proepper
authors.affiliation: Institute of Neuroanatomy, Eberhard Karls University Tübingen Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm UniversityUlm, Germany; Department of Neurology, Ulm UniversityUlm, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schmeisser
authors.affiliation: Department of Neurology, Ulm University Ulm, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Institute of Biophysics, Ulm University Ulm, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Michaelis
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University Ulm, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
keywords: FUS; RNA-binding proteins; STORM; amyotrophic lateral sclerosis; frontotemporal dementia; local translation; super-resolution microscopy; synapse
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