ALS progression mechanism unravelled
doi:10.1038/nindia.2015.159 Published online 27 November 2015
Last summer's Ice Bucket Challenge — dumping a bucket of ice water on someone's head — that went viral on social media, helped promote awareness of Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease affecting people worldwide. Researchers at New Delhi's International Centre for Genetic Engineering and Biotechnology (ICGEB) now report discovering the likely mechanism that leads to the progression of this debilitating motor neuron disease1.
Mishandled proteins within nerve cells lead to a gradual accumulation of abnormal forms of these proteins in the cells eventually causing nerve cells to die. This results in muscle weakness and loss of physical function. A cure or treatment that halts or reverses ALS is not yet available. On a molecular level, the "TATA binding protein Associated Factor 2N", otherwise known as TAF15 protein, has been identified as playing a key role in ALS progression, Neel Sarovar Bhavesh, lead researcher told Nature India.
"The natural role of TAF15 is to regulate the expression of genes by interacting with their mRNA products and regulating alternate splicing," he said. Compromised effects of TAF15 on transcription and alternative splicing lead to neuronal cell degeneration in TAF15-associated ALS. But the exact mechanism by which it does this was elusive till date.
The ICGEB scientists have shown for the first time how an RNA Recognition Motif (RRM) domain of TAF15 binds to its preferred RNA sequences through a very rare mode of interaction. Bhavesh explains this complex interaction by drawing an analogy from the game of cricket. "At the atomic level, the RRM was found to form a "clamp" and grip the loopy region of an RNA similar to how a bowler’s hand clenches the seam of a cricket ball."
The researchers say the discovery of this mechanism sheds new light on the molecular basis of ALS progression and also provides a fresh outlook into modes of RNA recognition by the RRM containing proteins.
1. Kashyap, M. et al. Structural delineation of stemloop RNA binding by human TAF15 protein. Sci. Rep. (2015) doi: 10.1038/srep17298