FUS homolog TAF15 may be the fifteenth gene associated with ALS according to a new study published this week.  The international team, led by University of Pennsylvania's Aaron Gitler, PhD, found mutations in the gene in 5 out of 1,262 patients tested.  Recently implicated in ALS, TAF15 helps to produce proteins appropriately in many cell types including motor neurons.  Studies are still needed in larger groups of people with ALS to determine whether mutations in TAF15 are linked to the disease.

Keeping score. Researchers looked for RNA processing proteins that when produced in baker’s yeast, clumped up and turned lethal.  The team identified 13 proteins (green) that shared similiarities to ALS-linked FUS and TDP-43.  Adapted from Couthouis et al. (2011).  Courtesy of the National Academy of Sciences Press. All rights reserved.

References

Couthouis, J., et al. (2011) A yeast screen predicts new candidate genes for amyotrophic lateral sclerosis.  Proceedings of the National Academy of Sciences. doi 10.1073/pnas.1109434108  Abstract | Full Text

Ticozzi, N., et al. (2011) Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis.  American Journal of Medical Genetics Part B:  Neuropsychiatric Genetics, 156(3): 285-290. Abstract | Full Text (Subscription Required)

The splice of life. Researchers discovered that the protein TDP-43 (above) regulated the assembly or stability of more than 1000 RNAs in the center of the mouse brain. Image: Emw, Wikimedia Commons.

TDP-43 helps ensure proteins are produced appropriately by regulating the processing and translation of RNAs.  But in over 90% of people with ALS, TDP-43 builds up in the cytoplasm of cells of the brain and spinal cord.  The role of TDP-43 in ALS however remains controversial.

To try and figure out what role if any TDP-43 could play in the disease, researchers at the University of California at San Diego (UCSD) turned to crosslinking, immunoprecipitation and high-throughput sequencing (CLIP-seq) to obtain a comprehensive list of genes that may be regulated by TDP-43 in the brain. 

The team found that nearly one third of all genes in the mouse brain may be regulated at least in part by TDP-43.  And, within the center of the brain, more than 1000 RNAs required TDP-43 for appropriate assembly or stability.

The study is published this week in Nature Neuroscience.

In future, the UCSD scientists hope to identify a subset of these genes that may contribute to the onset or progression of ALS due to mislocalized TDP-43.  These discoveries could inspire new therapeutic strategies for the disease.

Reference

Polymenidou M et al. (2006) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43 . Nature Neuroscience, 14(4), 459-468.  Abstract | Full Text

Further Reading

Tollervey, J.R. et al. (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nature Neuroscience, 14(4), 452-458. Abstract | Full Text