Upregulated Autophagy - Possible answer to SCA3 Motor Neuron Disorder | Anushka Chakravorty

Interview

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Neurons communicate with each other through synaptic connections and if these connections are lost or damaged, entire networks of neurons might get affected leading to brain damage. Damaged or dysfunctional synapses might subsequently lead to a class of neurodegenerative disorders, termed as synaptopathies. In our study, we showed that a fruit fly model of one such neurodegenerative condition, called Spinocerebellar Ataxia Type 3, is associated with motor neuron dysfunction and behavioural defects, such as locomotion deficits and reduced lifespan. In this particular neurodegenerative disorder (ND), a deubiquitinase called Ataxin-3 harbouring poly glutamine repeats, accumulates in the form of aggregates in or around the nucleus, leading to cellular dysfunction and pathology ranging from gait ataxia to peripheral muscular atrophy. To better understand such motor coordination defects, we studied the synapses formed by motor neurons (which are called neuromuscular junctions (NMJs)) in flies that harboured the mutant form of Ataxin-3 for detailed understanding. Indeed, we found impairment of NMJ morphology and function along with reduced proteostasis in these synapses. Autophagy is one of the important proteostasis pathways in the synapses. In this pathway, double-membraned vesicles called autophagosomes form de novo around the misfolded protein cargo and capture it. These vesicles then fuse with lysosomes to degrade the cargo, and the contents are released into the cytoplasm for reuse. Interestingly, we overexpressed one of the key core autophagy proteins, called Atg8a tissue-specifically in the motor neurons, and found that the behavioural deficits and synaptic dysfunction were partially rescued. Thus, our genetically amenable system provides a tool to enhance our understanding of synaptopathies for not just polyglutamine repeat-associated neurodegenerative diseases, but motor-neuron disorders in general.

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