Regulation of ageing by electrical synapses in the Nematode Caenorhabditis elegans
View/ Open
Date
25/11/2019Author
Vladis, Nathalie Alexandra
Metadata
Abstract
Electrical synapses formed by gap junctions are abundant in nervous systems and
critical for brain function. They allow not only the exchange of ions, but also of
metabolites and second messengers and have been implicated in the transmission of
damage or death signals between cells. However, it was not known if they play a role
in the processes that regulate neural ageing and lifespan.
In my PhD project, I sought to explore if gap junctions affect ageing and lifespan using
the roundworm Caenorhabditis elegans. Gap junctions are present in virtually all cells
and tissues of C. elegans and are formed by twenty-five innexin genes encoding gap
junction subunits. I assayed lifespan of loss-of-function mutants of most C. elegans
innexins and discovered that innexins have a significant impact on lifespan, some
leading to an extension of lifespan while others accelerate the ageing process and
shorten lifespan. Specifically, null mutations in unc-9, the most widely expressed
innexin in the nervous system, extended lifespan by up to thirty-five percent
compared to wild-type. Its effect on longevity is likely due to the intercellular coupling
provided by UNC-9, as loss of the UNC-9-regulating stomatin unc-1 extends lifespan in
the same manner. In follow-up experiments, I used RNA interference to ask if UNC-9
acts in specific sets of cells to modulate longevity. Its removal from glutamatergic
neurons led to an increase in lifespan, whereas I found no effects of unc-9 knock-down
in GABAergic, dopaminergic or cholinergic neurons or muscle. Interestingly, my RNAi
results point to a potential neural circuit mostly consisting of mechanosensory and
interneurons where coupling via UNC-9 limits lifespan.
Subsequently, I exposed unc-9 mutants to a battery of tests which examined the
animals’ healthspan and resistance to oxidative stress. These assays revealed that unc-9 mutants stay motile and responsive for longer. Furthermore, our results of
experiments with pro- and anti- oxidative agents suggest that direct coupling through
UNC-9 could facilitate the transmission of oxidative stress-linked signals that
negatively impact longevity. We are only beginning to appreciate the diverse and complex roles of gap junctions in
brain functioning and their roles in development and neuronal injury. My work for the
first time reveals that gap junction coupling also regulates ageing and longevity.