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Synaptic FUS Localization During Motoneuron Development and Its Accumulation in Human ALS Synapses
Dhruva Deshpande1, Julia Higelin2, Michael Schoen2
1Institute of Biophysics, Ulm University, Ulm, Germany.
Frontiers in Cellular Neuroscience
|June 28, 2019
Summary
Mutations in the fused in Sarcoma (FUS) gene cause amyotrophic lateral sclerosis (ALS). This study reveals FUS shifts from postsynaptic to axonal terminals during synapse development, with mutant FUS accumulating abnormally in ALS synapses.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Mutations in the fused in Sarcoma (FUS) gene are linked to amyotrophic lateral sclerosis (ALS).
- FUS is primarily a nuclear protein but also localizes to neuronal somatodendritic regions.
- Motoneurons are critically affected in ALS, and synaptic FUS localization is poorly understood.
Purpose of the Study:
- To investigate the localization of FUS within motoneuron synapses during development and in ALS.
- To determine if FUS localization changes during synaptic maturation.
- To examine the impact of FUS mutations on synaptic FUS accumulation and aggregation.
Main Methods:
- Super-resolution microscopy was employed to visualize FUS localization in pre- and postsynaptic compartments of rodent and human motoneuron synapses.
- Analysis included synapses from developing and mature rodent models.
- Human motoneurons derived from induced pluripotent stem cells (iPSCs) from healthy controls and ALS patients with FUS mutations were studied.
Main Results:
- FUS localization in rodent synapses changes with maturation, shifting from predominantly postsynaptic in early stages to entirely axonal terminal in mature synapses.
- In healthy human motoneurons, FUS is mainly postsynaptic during early development.
- ALS patient motoneurons with aggressive FUS mutations showed increased synaptic accumulation of mutant FUS and aggregation of synaptic proteins Bassoon and Homer1.
Conclusions:
- Synaptic FUS exhibits dynamic localization during synaptogenesis, potentially playing roles in both dendritic and axonal compartments.
- Mutant FUS accumulation at synapses suggests a gain-of-toxic function mechanism in ALS pathogenesis.
- Aberrant synaptic FUS aggregation may contribute to the neurodegeneration observed in FUS-linked ALS.
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