Synaptic defects in adult drosophila motor neurons in a model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons in the brain and spinal cord. Like other neurodegenerative diseases, defects in synaptic integrity are among the earliest hallmarks of ALS. However, the specific impairments to synaptic integrity remain unclear. To better understand synaptic defects in ALS, we expressed either wild-type or mutant Fused in Sarcoma (FUS), an RNA binding protein that is often mis-localized in ALS, in adult motor neurons. Using optogenetic stimulation of the motor neurons innervating the Ventral Abdominal Muscles (VAMs), we found that expression of mutant FUS disrupted the functional integrity of these synapses. This functional deficit was followed by disruption of synaptic gross morphology, localization of pre- and post-synaptic proteins, and cytoskeleton integrity. We found similar synaptic defects using the motor neurons innervating the Dorsal Longitudinal Muscles (DLMs), where expression of mutant FUS resulted in a progressive loss of flight ability along with disruption of active zone distribution. Our findings uncover defects in synaptic function that precede changes in synaptic structure, suggesting that synaptic function is more sensitive to this ALS model. Highlighting the earliest synaptic defects in this disease model should help to identify strategies for preventing later stages of disease progression.