Synaptopathy of one of the major excitatory synapses, i.e., the glutamatergic synapse, has been reported in several neurodegenerative and neurodevelopmental disorders, including autism spectrum disorders (ASD), Down syndrome (DS), and intellectual disabilities (ID) ( Südhof, 2008 Hussain et al., 2014 Tang et al., 2014 Volk et al., 2015). The term “synaptopathy” was introduced to include brain disorders arising as a result of synaptic dysfunction ( Li et al., 2003). Properly functioning synapses are critical to the integrity of neuronal networks in the brain, and any dysfunction of synapses may lead to the manifestation of neurodegenerative disorders ( Lepeta et al., 2016 Bae and Kim, 2017). Synapses, the terminal ends of neurons, are highly complex structures.
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. Our study reveals that overexpression of the autophagy-related protein Atg8a rescued behavioral defects. Autophagy, one of the key proteostasis pathways, is known to be impaired in the case of several synaptopathies. Detailed characterization of larval glutamatergic neuromuscular junctions (NMJs) revealed defects in morphological features along with compromised NMJ functioning. Furthermore, defects in eclosion and lifespan were observed in adult flies. 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. In this study, we indicated that a Drosophila model of MJD recapitulates characteristics of neurodegenerative disorders marked by motor neuron dysfunction. While the polyQ repeat mutant protein ataxin-3 is implicated in MJD, it is unclear how it leads to impaired synaptic function. 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. Synaptopathies are neurodegenerative diseases that are associated with synaptic dysfunction and often display compromised proteostasis.
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. 3Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.2Chronobiology and Behavioural Neurogenetics Laboratory, Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.1Autophagy Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.Anushka Chakravorty 1, Ankit Sharma 2, Vasu Sheeba 2 * and Ravi Manjithaya 1,3 *
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