A discovery that might improve treatment options for patients with neurodegenerative diseases has been made by scientists from King’s College London and the University of Bath in the UK.
This discovery centers on a molecule that plays an important role in nerve cell development and is known to contribute to disease when it malfunctions. Previously, this molecule was thought to be restricted to the nucleus of the cell (the organelle containing a cell’s DNA and separated from the rest of the cell by a membrane) but this new study confirms an earlier finding by the same team according to which it can also be found in the cytoplasm (the watery interior of a cell). The study also demonstrates for the first time that the cytoplasmic pool of this protein is functionally active.
This discovery has important implications for research on neurodegenerative diseases such as Alzheimer’s disease and motor neuron disease.
The discovery, described in Current biology was carried out by Professor Corinne Houart of King’s College London in collaboration with Dr Nikolas Nikolaou of the Department of Life Sciences in Bath.
Loss of nerve function
Scientists have known for some time that splicing proteins – the molecules studied in this research – can sometimes aggregate and form insoluble complexes in the cytoplasm of the cell, and that these complexes can interfere with the function of a neuron (nerve cell), eventually causing the neuron to lose function and degenerate. However, this study is the first to show that a major splicing protein can be found in protein/messenger RNA complexes (called RNA granules) in the axons of nerve cells.
Axons are the long projections that carry electrical impulses away from the body of the nerve cell, connecting neurons to neighboring neurons or transmitting information from neurons to body tissues (eg, muscle or skin). Axon dysfunction is known to be the cause of many progressive neurological disorders, so the discovery of splicing proteins in this part of the nerve cell provides insight into the mechanism that might give rise to the disease.
Shaping the messenger RNA molecule
The researchers found that the splicing protein SNRNP70 binds to strands of messenger RNA (mRNA) and then shapes them. These strands carry the genetic information of DNA from the nucleus of a cell to the cytoplasm of the cell. The information carried by mRNA is used to create other proteins, the building blocks of life. The team also found that the splicing protein is necessary for mRNA to move from the nerve cell body along axons to more peripheral parts of a neuron.
Commenting on the research, which uses zebrafish as a genetic model system, Dr Nikolaou said: “When we interfered with the function of the splicing protein, we saw that motor neurons were not forming well. They failed to make connections where they should have, and they lost other important connections. This type of behavior is also seen in human neurodegeneration. However, when SNRNP70 was reintroduced only into the cytoplasm and axons of these neurons, it was enough to restore motor connectivity and neuronal function once once more.
Although a small freshwater fish, the zebrafish is a species with a nervous system remarkably similar to that found in humans.
In the next phase of this research, Dr. Nikolaou plans to explore the precise function of this protein in axons. “We know that proteins interact with other proteins, so what proteins does this molecule interact with? And what happens when we remove these complexes from the cytoplasm – how does that affect neuronal function?”
He added: “Now that we know that these types of molecules have a function outside the nucleus, we will have to approach neurodegeneration from a different angle, asking ourselves how these pathogenic aggregates interfere with the function of these proteins not only in the nucleus but also in the cytoplasm, and what role they play in the degradation of neurons. It’s something we hadn’t thought of before.
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