Babcock, D. T. | Search bioRxiv

bioRxiv2026

Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model

Mutations in Fused in Sarcoma (FUS), a RNA binding protein, cause Amyotrophic Lateral Sclerosis (ALS). ALS is an aggressive neurodegenerative disease resulting in motor neuron degeneration. Defects in synaptic integrity precede neuronal loss in ALS, but the mechanisms responsible for these early synaptic defects are unclear. To investigate early synaptic defects associated with ALS, we expressed an ALS-linked variant of human FUS in adult motor neurons and assessed synaptic pathology at the neuromuscular junction (NMJ). Here we highlight the accumulation of FUS-positive aggregates at synaptic terminals and subsequent reduction in microtubule stability. We show that inducing autophagy via expression of Rab1 or Fragile-X Mental Retardation Protein 1 (FMR1), or treatment with Rapamycin reduces aggregate formation and restores synaptic structure and function. These findings reveal the utility of inducing autophagy to address early synaptic dysfunction in an ALS model and demonstrate a potential therapeutic target to preventing later stages of disease progression.

neuroscience↗

bioRxiv2026

The Vesicular Glutamate Transporter Modulates Sex and Region-Specific Differences in Dopaminergic Neuron α-Synuclein Toxicity by Modifying Cytosolic Dopamine Levels

Parkinsons disease disproportionately affects males; however, the cause of this sex difference is unknown. We found that expressing mutant -synuclein A53T in Drosophila dopamine neurons recapitulates the sex differences observed in human Parkinsons disease patients. Male flies exhibited greater age-related motor impairment and more severe dopamine neuron degeneration than females. Selective masculinization of female dopamine neurons via knockdown of the sex determination gene Transformer eliminated the observed sex differences in locomotor ability and neurodegeneration by increasing the severity of motor defects and degeneration in females. Transformer knockdown in dopamine neurons also reduced total vesicular glutamate transporter staining in the brain. Direct knockdown of the vesicular glutamate transporter in female dopamine neurons expressing -synuclein A53T exacerbated motor dysfunction, altered mitochondrial dynamics, and accelerated dopamine neuron degeneration. Increasing cytosolic dopamine via knockdown of the vesicular monoamine transporter or increasing total dopamine levels via levodopa treatment phenocopied vesicular glutamate transporter knockdown; furthermore, reducing total dopamine via alpha-methyl-p-tyrosine treatment protected against vesicular glutamate transporter knockdown. These results support a model in which lower VGLUT levels in dopamine neurons result in higher levels of cytosolic dopamine, which leads to dopamine mediated mitochondrial dysfunction and increased susceptibility to -synuclein A53T toxicity.

neuroscience↗