Defects in synapse structure and function precede motor neuron degeneration in Drosophila models of FUS-related ALS.

Authors

Mohammad Shahidullah, Farber Institute for Neurosciences, Thomas Jefferson UniversityFollow
Sylvain J Le Marchand, Vanderbilt University; Thomas Jefferson UniversityFollow
Hong Fei, Department of Neuroscience, Thomas Jefferson UniversityFollow
Jiaming ZhangFollow
Udai Bhan Pandey, Louisiana State University Health Sciences Center, New Orleans
Matthew B. Dalva, Thomas Jefferson UniversityFollow
Piera Pasinelli, Thomas Jefferson UniversityFollow
Irwin B. Levitan, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

12-11-2013

Comments

This article has been peer reviewed. It is the author’s final published version in Journal of Neuroscience

Volume 33, Issue 50, December 2013, Pages 19590-19598.

The published version is available at DOI: 10.1523/JNEUROSCI.3396-13.2013. Copyright © Society for Neuroscience

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that leads invariably to fatal paralysis associated with motor neuron degeneration and muscular atrophy. One gene associated with ALS encodes the DNA/RNA-binding protein Fused in Sarcoma (FUS). There now exist two Drosophila models of ALS. In one, human FUS with ALS-causing mutations is expressed in fly motor neurons; in the other, the gene cabeza (caz), the fly homolog of FUS, is ablated. These FUS-ALS flies exhibit larval locomotor defects indicative of neuromuscular dysfunction and early death. The locus and site of initiation of this neuromuscular dysfunction remain unclear. We show here that in FUS-ALS flies, motor neuron cell bodies fire action potentials that propagate along the axon and voltage-dependent inward and outward currents in the cell bodies are indistinguishable in wild-type and FUS-ALS motor neurons. In marked contrast, the amplitude of synaptic currents evoked in the postsynaptic muscle cell is decreased by >80% in FUS-ALS larvae. Furthermore, the frequency but not unitary amplitude of spontaneous miniature synaptic currents is decreased dramatically in FUS-ALS flies, consistent with a change in quantal content but not quantal size. Although standard confocal microscopic analysis of the larval neuromuscular junction reveals no gross abnormalities, superresolution stimulated emission depletion (STED) microscopy demonstrates that the presynaptic active zone protein bruchpilot is aberrantly organized in FUS-ALS larvae. The results are consistent with the idea that defects in presynaptic terminal structure and function precede, and may contribute to, the later motor neuron degeneration that is characteristic of ALS.

Recommended Citation

Shahidullah, Mohammad; Le Marchand, Sylvain J; Fei, Hong; Zhang, Jiaming; Pandey, Udai Bhan; Dalva, Matthew B.; Pasinelli, Piera; and Levitan, Irwin B., "Defects in synapse structure and function precede motor neuron degeneration in Drosophila models of FUS-related ALS." (2013). Department of Neuroscience Faculty Papers. Paper 10.
https://jdc.jefferson.edu/department_neuroscience/10