Just like Indian streets, our brains are highly-wired territory, crisscrossed with trillions of neuronal circuits created by billions of neurons. By releasing chemicals called neurotransmitters via synaptic vesicles (SV), each presynaptic neuron communicates with itself and thousand other neurons at junctures called synapses. Interrupting this discourse can cause neuronal diseases.

Proteins necessary for these communications are made in the cell body and transported towards the synaptic zone by transport vesicles, the precursors of SVs. A research group led by Sandhya P. Koushika, Associate Professor, Tata Institute of Fundamental Research, Mumbai, recently discovered the role of three key regulators in the sorting and transport of SV proteins in neurons of the tiny roundworm Caenorhabditis elegans.

Samarjit Bhattacharyya, Professor, Indian Institute of Science Education and Research (IISER) Mohali, says, 

Understanding the mechanisms of SV biogenesis is an exciting and important area to study in neuroscience. SVs, filled with neurotransmitters mediate synaptic transmission, but how SV proteins are sorted to the presynaptic nerve terminals is not yet well understood.

The neuron’s cell body is a metabolic hub with an efficient parceling system for delivering organelle-specific metabolites performing different cellular functions. Adaptor protein (AP)-3 excludes lysosomal proteins from SV precursors and Koushika lab previously discovered that the C. elegans protein LRK‑1 (similar to mammalian LRRK2 protein) excludes Golgi resident proteins from SV precursors in cooperation with AP‑3 and another sorter AP‑1.

The researchers in this study first examined the composition of SV precursors and found that a small number of them briefly co-transport lysosomal proteins along with SV proteins before these are sorted into respective compartments. Then they created mutant worms with altered functions for LRK‑1, AP‑3, and other selected genes, then tracked the movement of these vesicles in both mutant and normal neurons using static and time-lapse imaging.

Compared to billions of neurons in humans, C. elegans has only around 300. Sravanthi S. P. Nadiminti, the first author of this study notes, 

The power of the C. elegans genetic model along with its transparent body offers us control over manipulating gene function and visualising cell biological processes in vivo.

They discovered that without LRK‑1 and AP‑3, SV and lysosomal proteins don’t get sorted and travel together further as more UNC-104 (similar to mammalian KIF1A), molecular motor proteins critical for pulling SV precursors along the axon, get recruited. This is more prominent without LRK‑1 as it regulates AP‑3. They further show that in the absence of AP‑3 — SYD‑2 (similar to mammalian Liprin‑α protein), another sorter that binds to UNC-104 — takes over and likely links the sorting and transport of SV proteins.

In addition, SYD‑2 also ensure that SV precursors travelling along axons (the longest protrusions of neurons) don’t mistakenly go towards dendrites (shorter protrusions of neurons) by regulating AP‑3 and AP‑1. Nadiminti explains, ​“Both SYD‑2 and the AP‑1 are needed to facilitate the entry of what we think are SV proteins missorted into dendritically targeted vesicles instead of axonal ones.” 

Bhattacharyya comments, ​“There is increasing evidence that deficiencies or defects in SV proteins might underlie neurological disorders such as schizophrenia, Alzheimer’s disease and Parkinson’s disease. Therefore, this study is a step forward towards understanding the role of these events in the normal and diseased brain.” 

This work was done in collaboration with researchers from Rutgers University, USA. Koushika concludes, 

We will continue our work in uncovering both trafficking routes and pathways in synaptic vesicle biogenesis, maturation and transport.