Scientists at King’s College London and the University of Bath in the U.K., report they have discovered how a molecule plays a critical role in nerve cell development. This finding has important implications for research into neurodegenerative disorders such as Alzheimer’s and motor neuron disease.
The findings are published in the journal Current Biology in an article titled, “Cytoplasmic pool of U1 spliceosome protein SNRNP70 shapes the axonal transcriptome and regulates motor connectivity.”
“Regulation of pre-mRNA splicing and polyadenylation plays a profound role in neurons by diversifying the proteome and modulating gene expression in response to physiological cues,” wrote the researchers. “Although most of the pre-mRNA processing is thought to occur in the nucleus, numerous splicing regulators are also found in neurites. Here, we show that U1-70K/SNRNP70, a component of the major spliceosome, localizes in RNA-associated granules in zebrafish axons. We identify the extra-nuclear SNRNP70 as an important regulator of motor axonal growth, nerve-dependent acetylcholine receptor (AChR) clustering, and neuromuscular synaptogenesis.”
The discovery was made using zebrafish as a genetic model system by Corinne Houart, PhD, professor of developmental neurobiology at King’s College London, working with Nikolas Nikolaou, PhD, from the department of life sciences at Bath.
Scientists have known for some time that splicing proteins can sometimes aggregate and form insoluble complexes in the cell’s cytoplasm, 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 within protein/messenger RNA complexes (known as RNA granules), within the axons of nerve cells.
The researchers found that the splicing protein SNRNP70 binds to, and subsequently shapes, strands of mRNA. These strands carry genetic information from the DNA in a cell’s nucleus to the cell’s cytoplasm. The information carried by mRNA is used to create further proteins, the building blocks of life. The team also discovered that the splicing protein is needed in order for mRNA to move from the nerve cell body along axons to more peripheral parts of a neuron.
“When we interfered with the function of the splicing protein, we saw motor neurons didn’t form well,” explained Nikolaou. “They failed to establish connections where they should have, and they lost other important connections. This sort of behavior is also observed in human neurodegeneration. However, when SNRNP70 was re-introduced only in the cytoplasm and axons of these neurons, it was sufficient to restore motor connectivity and neuronal function once again.”
The researchers plan to explore the precise function of this protein in axons.
“Now we know these types of molecules have a function outside the nucleus, we will need to approach neurodegeneration from a different angle, asking ourselves how these disease-causing 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 breakdown of neurons. This is something that hasn’t been thought about before,” concluded Nikolaou.