Glutamatergic Synapse Dysfunction in Drosophila Neuromuscular Junctions Can Be Rescued by Proteostasis Modulation

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Synaptopathies, neurodegenerative diseases linked to synaptic dysfunction, often involve impaired proteostasis.
• Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is a progressive neurodegenerative condition affecting motor neuron synapses.

Purpose of the Study:

• To establish a *Drosophila* model of MJD to investigate the mechanisms of glutamatergic neuromuscular junction (NMJ) dysfunction.
• To explore the role of proteostasis, specifically autophagy, in MJD-related synaptopathies.

Main Methods:

• Generated a *Drosophila* model expressing mutant ataxin-3 protein with 78 polyQ repeats in motor neurons.
• Assessed behavioral phenotypes (locomotion, eclosion, lifespan) and characterized larval glutamatergic NMJs.
• Investigated the effect of overexpressing the autophagy-related protein Atg8a on MJD model phenotypes.

Main Results:

• The *Drosophila* MJD model exhibited impaired locomotion, reduced eclosion rates, and shortened lifespan.
• Morphological and functional defects were observed at glutamatergic NMJs.
• Overexpression of Atg8a significantly rescued the observed behavioral deficits.

Conclusions:

• The *Drosophila* MJD model effectively recapitulates key features of neurodegenerative synaptopathies.
• Autophagy plays a crucial role in mitigating MJD-related synaptic and behavioral impairments.
• This model provides a valuable platform for screening therapeutic targets for synaptopathies.