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Molecular mechanisms underlying synaptic maintenance and rejuvenation

Periodic Reporting for period 1 - HEALTHYSYNAPSES (Molecular mechanisms underlying synaptic maintenance and rejuvenation)

Reporting period: 2016-03-01 to 2018-02-28

Diseases of the brain like dementias and other neurodegenerative conditions (for e.g. Parkinson's) are becoming a more prevalent aspect of our society. As our lifespan increases, the prevalence is only going to increase. So it has become crucial that we understand the mechanisms that are affected in brain disorders and explore means by which we may be able to tackle these disorders by reducing or eliminating their degenerative effects. Within the brain, it has become clear that proper function depends on the fidelity of synaptic transmission. Furthermore, the failure of synapses is an early and key phenomenon in neurodegenerative disorders. Therefore, I am interested in understanding how accurate synaptic function is maintained throughout lifetime. My interest was focused on the maintenance of protein homeostasis at the synapse through the process of autophagy – a group of cellular mechanisms that are involved in the degradation of dysfunctional proteins and other cytoplasmic entities. I wanted to develop the links between autophagy and neuronal function. I wanted to see whether changes in autophagy could be linked to the dysfunction seen at synapses and all the associated phenotypes seen in the brain during ageing and disease conditions. I was also interested in identifying the specific autophagic pathways active at the synapse and to identify synaptic proteins that has unique roles in modifying synaptic autophagy. Furthermore, I wanted to generate tools that could help us study and control autophagy at the synapse with precision. I believe that the better understanding of synaptic autophagy that we have gained from this project will help us harness the power of autophagy as a therapeutic means of maintaining synaptic function and potentially restoring altered synaptic function in disease conditions.
I have developed and deployed several tools for studying autophagy specifically at the synapse. I used fluorescent markers that allow us to track autophagy and measure the levels of autophagy. We have developed a Correlative Light and Electron Microscopy (CLEM) in Drosophila that allow us to visualize autophagy with unprecedented clarity. Furthermore, electrophysiological and behavioural assays have allowed me to build the links between autophagy to synaptic and neuronal function. I observe that autophagy is affected in certain age-related diseases conditions. Interestingly, synaptic proteins are responsible for the alteration seen suggesting that there are synapse specific autophagic processes at work. I find that autophagy at the synapse may be a very specific form of autophagy, involving several specific synaptic proteins. These proteins include synaptojanin, which regulates macroautophagy and auxilin, which regulates microautophagy.
Under certain conditions, autophagy is reduced and this can be linked to neurodegeneration while in other conditions, specific types of autophagy are upregulated. These data suggest that both an up regulation and down regulation of autophagic mechanisms can have deleterious effects on synapses and neurons. My optogenetic tools also show that increasing autophagy specifically at the synapse can have effects on synapse function and growth. Given that both increased and decrease synaptic autophagy seems to be disadvantageous, it seem synaptic autophagy is a very tightly regulated process. The age and disease condition dependent change in synaptic function is also correlated with changes in synaptic electrophysiology and behavioural alterations (for e.g. decreased motor function) that suggest nervous system dysfunction. In order to deepen our understanding of synaptic autophagy, a genetic screen of nearly 5000 Drosophila mutants was conducted and several genes have been isolated that specifically rescue dysfunctional synaptic autophagy. In my future studies, I will use these candidate genes to gain an even deeper understanding of the network of synaptic autophagy present in the nervous system.
These results have been presented in oral and poster format at several national and international conferences. Furthermore, we have several manuscripts in preparation describing these findings that will be published soon.
My results highlight role of autophagy in the modulation of synaptic and neuronal function in neurodegenerative conditions and aging. The results also suggest that autophagy may be valuable tool that can be modulated in order to remove dysfunctional cellular components that cause diseases. The identification of distinct autophagic processes present at the synapse is a very important contribution to our work. This is the first time that very distinct, compartmentalized forms of autophagy have been described. The synaptic proteins that we have identified are potential drug targets that will allow us to sensitively modulate autophagy such that we can use autophagy to restore and rejuvenate synapses in disease conditions. As mentioned, Synapse function is affected in nearly every major neurodegenerative conditions and more than 15 million Europeans and many more millions worldwide are expected to be affected by these conditions in the near future. Therefore, the improvement of synapse function due to the better understanding of synaptic autophagy derived from this project has wide reaching health consequences for our society.
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