Scientists reveal ALS drug target
8 Jun 2015
Amyotrophic lateral sclerosis (ALS) - commonly referred to as motor neurone disease (MND) in the UK - is a debilitating neurodegenerative disorder that leads to paralysis and death due to the loss of motor neurones in the brain and spinal cord.
Now, researchers from the Gladstone Institutes and the University of Michigan, US have identified a cellular mechanism that can be targeted to treat ALS, while also finding potential for treating frontotemporal dementia - a related disease.
According to the research team, a primary feature of ALS is an accumulation of the protein TDP43, too much of which is toxic to cells.
“This is the first time we’ve been able to link this natural monitoring system to neurodegenerative disease
Senior investigator Steven Finkbeiner
In the study, the researchers identified another protein, hUPF1, which helps to stabilise TDP43 - thereby preventing cell death.
“TDP43 is a ’Goldilocks’ protein: too much, or too little, can cause cellular damage,” said first author Sami Barmada, an assistant professor of neurology at the University of Michigan Medical School and former post-doctoral fellow at Gladstone.
“Over 90% of ALS cases exhibit TDP43-based pathology, so developing a treatment that keeps protein levels just right is imperative,” Barmada said.
The study revealed that genetically increasing levels of hUPF1 extended neurone survival by 50-60%.
What’s more, the researchers also discovered that hUPF1 acts through a cellular surveillance system called nonsense mediated decay to keep TDP43 levels stable and enhance neuronal survival.
“Cells have developed a really elegant way to maintain homeostasis and protect themselves from faulty proteins,” said senior author Steven Finkbeiner, a senior investigator at the Gladstone Institute of Neurological Disease.
“This is the first time we’ve been able to link this natural monitoring system to neurodegenerative disease. Leveraging this system could be a strategic therapeutic target for diseases like ALS and frontotemporal dementia.”
Using its research, the team wants to develop a drug that can target nonsense medicated decay - by manipulating hUPF1 or through other proteins that affect this system - to influence levels of TDP43 and protect neurones.
’Ice bucket challenge’
ALS/MND was brought massively into the spotlight last year in the form of the ’Ice Bucket Challenge’ - in which people would video themselves pouring a bucket of icy water over their heads and then nominating a family member or friend to do the same.
According to statistics, the phenomenon helped raise almost $100 million (£65.6m) during August 2014 - compared with $2.7 million (£1.7m) for the same period in 2013.
Of all those who took part in the challenge, it was perhaps most famously completed by Professor Stephen Hawking, who has had ALS/MND for over 50 years.
