The enzyme Gemin3 was identified as the molecular 'bridge' between genes whose mutation or disruption causes amyotrophic lateral sclerosis (ALS), according to a new study in Nature's Scientific Reports.
ALS robs patients of their ability to walk, eat or breathe. The late-onset neurodegenerative disease destroys motor neurons, the long nerve cells in the brain and spinal cord that tell the muscles what to do. Signals from these nerves gradually stop reaching the muscles, which weaken and die. There is no cure for ALS, and, eventually, the disease is fatal.
Genetics contributes significantly to the development of ALS. Mutations in any of an ever-increasing list of genes have been identified to cause ALS with TDP-43, FUS and SOD1 featuring at the top considering that together they are responsible for a large percentage of ALS cases with a family history.
"We have been perplexed by the seemingly diverse functions of genes linked to ALS. The lack of commonality complicates the process for developing treatments that are broadly beneficial," said the study's lead researcher.
Through investigations on fruit flies, the research team were able to identify a gene whose mild perturbation was enough to trigger worsening of ALS symptoms caused by disruption of TDP-43, FUS or SOD1. The gene, named Gemin3, produces an enzyme offering researchers the possibility of tuning its function to ameliorate ALS symptoms.
Gemin3 has long been known for its alliance with the survival motor neuron (SMN) protein. A deficiency of SMN causes spinal muscular atrophy (SMA), a motor neuron disease that strikes infants. Gemin3's activity is crucial for building the splicing machinery which edits the cell's genetic instructions. Earlier discoveries of the research group linked Gemin3 to several key players in this delicate process.
Disruption of either TDP-43 or FUS enhance defects associated with Gemin3 loss-of-function. Gemin3-associated neuromuscular junction overgrowth was however suppressed. Sod1 depletion had a modifying effect in late adulthood.
Authors also show that Gemin3 self-interacts and Gem3ΔN, a helicase domain deletion mutant, retains the ability to interact with its wild-type counterpart. Importantly, mutant:wild-type dimers are favoured more than wild-type:wild-type dimers.
In addition to reinforcing the link between SMA and ALS, further exploration of mechanistic overlaps is now possible in a genetically tractable model organism. Notably, Gemin3 can be elevated to a candidate for modifying motor neuron degeneration.
Right now, the research team is determining whether targeting multiple players in the pathway uncovered by Gemin3 can ameliorate ALS, a result that can potentially pave the way for development of treatments that are effective to a broad swathe of ALS patients.
https://www.um.edu.mt/newspoint/news/features/2020/01/scientistsatumdiscoverlinkbetweenalsgenes
https://www.nature.com/articles/s41598-019-53508-4
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fsmn-complex-member&filter=22
Link between ALS genes identified!
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