Defects in Synapse Structure and Function Precede Motor Neuron Degeneration inDrosophilaModels of FUS-Related ALS

• DOI: 10.1523/jneurosci.3396-13.2013
• Publication Date: 2013-12-11T17:39:36Z
• Authors: Mohammad Shahidullah; Sylvain J. Le Mar...; Hong Fei; Jiaming Zhang; Udai Bhan Pandey; Matthew B. Dalva; Piera Pasinelli; Irwin B. Levitan
• Keywords: Motor Neurons; 0303 health sciences; Animal; Amyotrophic Lateral Sclerosis; Neurosciences; 610; Disease Models, Animal; 03 medical and health sciences; Disease Models; Nerve Degeneration; Synapses; Animals; RNA-Binding Protein FUS; Drosophila

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