Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder that affects approximately 1 in 50,000 individuals worldwide. ALS robs patients of their ability to walk, eat, or breathe. The disease destroys motor neurons, disrupting signals from these nerves, which gradually stop reaching the muscles—leading to muscle weakening and atrophy. Unfortunately, at present, there is no cure for ALS and the disease is eventually fatal. While scientists have identified much of the genetics behind this disease there is still a knowledge gap as to how many of these genes interact to initiate the disorder.
Now, a team of investigators from the University of Malta has discovered a molecular “bridge” between genes whose mutation or disruption causes ALS—the enzyme Gemin3. Findings from the new study were published recently in Scientific Reports through an article titled “SMN complex member Gemin3 self-interacts and has a functional relationship with ALS-linked proteins TDP-43, FUS and Sod1.” 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,” explained senior study investigator Ruben Cauchi, PhD, a senior lecturer at the University of Malta’s faculty of medicine & surgery and principal investigator at the University of Malta’s Centre for Molecular Medicine and Biobanking.
Through investigations on fruit flies, the research team was 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.
“Accumulating evidence has revealed a surprising molecular overlap between spinal muscular atrophy (SMA) and ALS. Here, we ask the question of whether Drosophila can also be exploited to study shared pathogenic pathways,” the authors wrote. “Focusing on motor behavior, muscle mass, and survival, we show that disruption of either TBPH/TDP-43 or Caz/FUS enhances defects associated with Gemin3 loss-of-function. Gemin3-associated neuromuscular junction overgrowth was however suppressed. Sod1 depletion had a modifying effect in late adulthood. We 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 favored more than wild-type:wild-type dimers.”
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.
“Our findings point to overlap in disease-causing mechanisms underlying each different ALS-causing gene. This can potentially unveil new targets for therapies that are effective in a wide range of ALS patients,” Cauchi noted.
Currently, 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 the development of treatments that are effective to a broad swathe of ALS patients.
“In addition to reinforcing the link between SMA and ALS, further exploration of mechanistic overlaps is now possible in a genetically tractable model organism,” the authors concluded. “Notably, Gemin3 can be elevated to a candidate for modifying motor neuron degeneration.”