LRRK2 & AP-3: Key Regulators of Synaptic Vesicle Traffic
Work done in the lab of Prof. Sandhya P Koushika at Tata Institute of Fundamental Research, Mumbai.
Sravanthi Nadiminti was an Integrated MSc-PhD student in Prof. Sandhya P Koushika’s lab at Tata Institute of Fundamental Research (TIFR), Mumbai. Sravanthi obtained her Bachelors (Hons.) in Biomedical Sciences from University of Delhi. She’s currently working as Postdoctoral Researcher in the lab of Prof. Volker Haucke at the Leibniz Institute for Molecular Pharmacology (FMP), Berlin.
Author Interview
How would you explain your research outcomes to the non-scientific community?
Neurons are special cells not only because they make up our brain but also because of their lengths and complex shapes. Neurons possess unique organelles known as Synaptic vesicles (SVs) that aid in neuronal function. SVs, like other organelles, have a set of proteins that are unique to them. SVs are acidic like lysosomes, and travel to synapses, parts of neurons where SVs release chemicals to enable neuronal function. Poor functioning of SVs is observed in several neurodegenerative disorders, thus making SVs vital for neuronal function, and therefore a healthy brain. Despite their importance in our everyday functions, our knowledge about the formation and transport of SVs to the synapses is relatively poor.
In any cell, proteins typically are present in the Golgi complex and are sorted from there to their final sites of action/destinations. This is analogous to how posts are sorted in our cities. All posts first arrive at the main post office from where they get further sorted to sub-post offices. At these substations, they are sorted further and transported to their destination, our addresses. Similarly inside cells, the Golgi complex acts as the main post office from where proteins are sorted to their target organelle/destination. How the different SV proteins are sorted from the Golgi complex to SVs is what remains poorly understood. In our study, we were able to show that SV proteins are not directly sorted from the Golgi complex to SVs. We show that proteins that make up another organelle called the lysosome, or lysosomal proteins, are sorted together with SV proteins from the Golgi complex. We think that SV and lysosomal proteins are sorted from the Golgi complex to a secondary sorting station that we call the SV-Lysosome. It is at the SV-Lysosome that SV and lysosomal proteins are further sorted and separated, thus forming SVs and lysosomes, which are then transported to synapses.
We show that the key molecules performing these sorting tasks include LRRK2, which when dysfunctional causes Parkinson’s disease in humans.
“Through basic research like our work, we will be able to understand the biology of a healthy neuron and the roles of various molecules that keep the neurons healthy, thereby enabling us to better understand the diseased conditions, thus opening up avenues for therapeutic interventions..”
How do these findings contribute to your research area?
Our work builds on our previously published work (Choudhary et al., 2017) and furthers understanding of how synaptic vesicle proteins are sorted and transported inside neurons. These results are very interesting as damages to both lysosomes and SVs are very common in neurodegenerative disorders. Through basic research like our work, we will be able to understand the biology of a healthy neuron and the roles of various molecules that keep the neurons healthy, thereby enabling us to better understand the diseased conditions, thus opening up avenues for therapeutic interventions.
What was the exciting moment during your research?
We had only hypothesised the presence of a secondary sorting station like SV-lysosomes, and at some level it seemed too good to be true for me. When we got the first evidence of their existence, especially when we saw so many of them in neuronal processes in which LRRK2 was mutated, it felt surreal. This was an exciting finding and we were very happy to see that data.
What do you hope to do next?
Our study has opened up the potential to pursue several avenues in understanding the cell biology of a neuron, especially of a diseased neuron. Since this work was done in C. elegans, I am currently working on understanding fundamental aspects of how human neurons work, so that in the future I can build on my PhD and postdoc training and expand the scope of my work to better understand the cell biology of Parkinson’s disease.
Where do you seek scientific inspiration from?
I have always loved biology. Even as a little kid, I would often read the anatomy section of an encyclopaedia, or anatomy textbooks that my parents bought for me seeing my interest in anatomy and biology. I would pour over these books trying to learn and understand more about life and the human body. My interest in cell biology sparked when I first learnt about protein trafficking through the early experiments by Günter Blobel during my Bachelors. When I started my PhD, I wanted to study cell biology, and after joining Sandhya’s lab, my interest in cell biology deepened. Through the kinds of questions Sandhya worked on, I started to appreciate fundamental science, an interest that sparked in me motivation to pursue a career in science.
How do you intend to help Indian science improve?
As a scientist, I think it is our responsibility to help improve how science is taught in our schools and to foster an interest in science in children. Throughout my PhD, I was able to share the excitement of science with children by engaging with them through TIFR Outreach programmes, Chai and Why? and National Science Day celebration, TIFR Founder’s Day events, and voluntary tutoring of students from 5th to 8th class around our hostel. I was also fortunate to work with Sandhya and others in busting myths surrounding COVID through an initiative called Indian Scientists Response to COVID (IndSciCov), for which I did translations and voice overs in a local language Telugu. I intend on continuing to actively engage in science communication and motivate more children to pursue degrees and careers in science.
Reference:
Nadiminti SSP, Dixit SB, Ratnakaran N, Deb A, Hegde S, Boyanapalli SPP, Swords S, Grant BD, Koushika SP. LRK-1/LRRK2 and AP-3 regulate trafficking of synaptic vesicle precursors through active zone protein SYD-2/Liprin-α. PLoS Genet. 2024 May 9;20(5):e1011253. doi: 10.1371/journal.pgen.1011253. PMID: 38722918; PMCID: PMC11081264. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11081264/
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