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

Abstract

Glutamate is the major excitatory neurotransmitter in the nervous system, and the Drosophila glutamatergic neuromuscular junctions (NMJs) offer a tractable platform to understand excitatory synapse biology both in health and disease. Synaptopathies are neurodegenerative diseases that are associated with synaptic dysfunction and often display compromised proteostasis. One such rare, progressive neurodegenerative condition, Spinocerebellar Ataxia Type 3 (SCA3) or Machado-Joseph Disease (MJD), is characterized by cerebellar ataxia, Parkinsonism, and degeneration of motor neuron synapses. While the polyQ repeat mutant protein ataxin-3 is implicated in MJD, it is unclear how it leads to impaired synaptic function. In this study, we indicated that a Drosophila model of MJD recapitulates characteristics of neurodegenerative disorders marked by motor neuron dysfunction. Expression of 78 polyQ repeats of mutant ataxin-3 protein in Drosophila motor neurons resulted in behavioral defects, such as impaired locomotion in both larval and adult stages. Furthermore, defects in eclosion and lifespan were observed in adult flies. Detailed characterization of larval glutamatergic neuromuscular junctions (NMJs) revealed defects in morphological features along with compromised NMJ functioning. Autophagy, one of the key proteostasis pathways, is known to be impaired in the case of several synaptopathies. Our study reveals that overexpression of the autophagy-related protein Atg8a rescued behavioral defects. Thus, we present a model for glutamatergic synapse dysfunction that recapitulates synaptic and behavioral deficits and show that it is an amenable system for carrying out genetic and chemical biology screens to identify potential therapeutic targets for synaptopathies.

Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement

“…These data suggest that MR6-26-2 partially improves proteostasis in the spinal cord of SOD1 G93A mice by facilitating the proper folding of mutant SOD1. We also analysed a neuromuscular junction pathology, since ebselen-derivative showed functional improvement of SOD1 G93A mice and proteostatic modulation rescued glutamatergic synaptic dysfunction in Drosophila neuromuscular junction 35 . Quantitative analysis of neuromuscular junctions in tibialis anterior muscles revealed that MR6-26-2 administration significantly ameliorated the denervation of skeletal muscles in SOD1 G93A mice (Fig.…”

Novel EAAT2 activators improve motor and cognitive impairment in a transgenic model of Huntington’s disease

“…Interestingly, dEAAT1 loss induced hyperexcitability is partially rescued by insertion of human EAAT2, suggesting the hyperexcitability behavior is at least in part a consequence of glutamate transport deficiency and EAAT-associated glutamate uptake functions are conserved between Drosophila and mammals ( Rival et al, 2004 ). Furthermore, Drosophila has been widely used as a model organism to test modulation of glutamate-mediated neurodegeneration ( Agrawal et al, 2005 ; Martin and Krantz, 2014 ; Chakravorty et al, 2022 ). For example, riluzole, an anti-excitotoxic agent that increases glutamate uptake has been shown to rescue memory deficits in Drosophila ( Matsuno et al, 2019 ).…”