A team led by researchers at the Centre for Developmental Neurobiology (CDN) has identified a protein that, when absent, leads to paralysis in fish. The findings reveal that the identified protein, SFPQ, is required for normal motor development and may have an important impact in understanding human motor neuron disorders, such as amyotrophic lateral sclerosis (ALS).
Motor neuron diseases are neurological disorders that selectively affect motor neurons, the nerve cells that extend from the spinal cord to control muscles and other organs of the body. The progressive degeneration of the motor neurons leads to weakness of muscles, causing increasing loss of mobility and difficulties with speech, swallowing and breathing. The team of researchers, led by Professor Corinne Houart from the CDN at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), and the MRC Centre for Neurodevelopmental Disorders (MRC CNDD), King’s College London, found that the absence of a protein called SFPQ, caused paralysis in the zebrafish model organism. Surprisingly, they also found that restoring the protein in the axons, the part of a neuron that sends the information, is enough to rescue the motor problem.
The findings were reported in a Neuron advance online publication on March 6, 2017.
Previous studies had shown that the SFPQ protein plays a key role in the cell nuclei. However, in their new study, the researchers show that this protein is also present in growing motor axons and is necessary outside of the nucleus to protect messenger RNAs during their transport to specific part of the growing neurons.
The observation of such a severe effect in the zebrafish, led the researchers to investigate whether the SFPQ gene may be affected in patients suffering from amyotrophic lateral sclerosis. For this, Professor Corinne Houart, teamed up with Professor Chris Shaw, at IoPPN, King’s College London, and Dr Ian Blair, from Macquarie University, Sydney. They did in fact find that the DNA of two patients had mutations in a very specific area of the protein, which were not changed in other human samples from healthy subjects. Moreover, the researchers also found that transferring the mutated human SFPQ, into zebrafish lacking its own SFPQ, leads to abnormal motor axons, suggesting relevance to pathology.
"Our findings support the exciting possibility of controlled maturation of transcripts inside the growing motor axons, providing a relative autonomy from the nucleus located centimeters away from the decisions needed. The results also challenge our classic view of splicing factor-related neurodegeneration, suggesting that pathology may be caused by loss of the cytoplasmic function of these proteins."
Professor Corinne Houart, senior author of the study
These findings provide a new understanding of the role of splicing factors in motor development, bringing new insights into RNA dynamics in this process. The connection between the role of SFPQ in motor development and its likely role in motor degeneration opens the possibility of a developmental origin for some neurodegenerative processes.
This work was supported by grants from the Medical Research Foundation; Medical Research Council, BBSRC, Wellcome Trust, Motor Neuron Disease Association and Heaton Ellis Trust, NHMRC and MND Australia.
Paper reference: Swapna Thomas-Jinu, Patricia M. Gordon, Triona Fielding, Richard Taylor, Bradley N. Smith, Victoria Snowden, Eric Blanc, Caroline Vance, Simon Topp, Chun-Hao Wong, Holger Bielen, Katherine L. Williams, Emily P. McCann, Garth A. Nicholson, Alejandro Pan-Vazquez, Archa H. Fox, Charles S. Bond, William S. Talbot, Ian P. Blair, Christopher E. Shaw and Corinne Houart. Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development. Neuron (on line April 6 2017). DOI: 10.1016/j.neuron.2017.03.026