Untangling Neurodegenerative Disease
A newly discovered molecular switch links RNA Polymerase II (RNAPII), a key genome-reading machinery, with neurodegenerative disorders, shedding light on how some of these devastating diseases may begin.
Understanding the ins and outs of transcription - a process by which cells read the genome – has been a life-long cause for University Professor Jack Greenblatt of the Donnelly Centre. Now his latest research, out December 23 in Nature, uncovers a tantalizing link between the key enzyme RNAPII and disorders such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).
Instructions for making our bodies are stored in genes, but the genetic code is only a blueprint and of little use on its own. In fact, scientists still can’t make complete sense of it. This is because the valuable text is interspersed with gibberish, all spelled out in the many combinations of DNA letters that only cells know how interpret. Cells interpret the code to turn genes into proteins, which are the building blocks of life.
Protein making begins with transcription that, akin to a cell’s Rosetta stone, turns the enigmatic genetic code into a more useful form – genes are transcribed into string-like RNA molecules that then serve as templates for building proteins. Cells have evolved a great number of molecular switches which ensure that transcription runs smoothly. Now Greenblatt and colleagues have discovered a crucial new switch that brings transcription to an end once the RNA has been synthesized.
The researchers found that RNA polymerase II (RNAPII), the key enzyme that puts the RNA together, becomes adorned at a particular place with chemical tags called methyl groups. In the absence of these tags, RNAPII can’t work with other proteins that help disengage the newly synthesized RNA molecule from the DNA original. This results in the snarling of the DNA and RNA strands, known as R-loops. If left unresolved, R-loops can lead to genome damage. In addition, they can also affect other steps in protein production such as RNA splicing, a process that brings the correct protein-coding parts together in the transcribed RNA. Failure to do so would cause ripples of badly formed proteins that would be damaging to the cell.
Greenblatt’s team found that methyl groups on RNAPII help the enzyme recruit a protein called SMN, known to be involved in SMA, a fatal motor neuron degenerative disease of infancy, and senataxin, which is sometimes mutated in ALS, a motor neuron disease that affects speaking, swallowing and eventually breathing. SMN and senataxin help untangle R-loops and release RNA from DNA so that protein synthesis may proceed.
“We’ve discovered a pathway that leads from modifications of RNAPII to how transcription is regulated, and remarkably it involves proteins involved in neurodegenerative disorders, suggesting that there is a link between the regulation of transcription and these diseases,” says Greenblatt, who is also a professor in the Department of Molecular Genetics.
This fascinating discovery is the first known link between a single molecular switch on the RNAPII and disease, opening the door to further research into understanding the causes of neurodegenerative disorders.