New Amyotrophic Lateral Sclerosis Drug Target Found

A cellular mechanism that can be targeted to treat amyotrophic lateral sclerosis has been identified by scientists from the Gladstone Institutes and the University of Michigan.

The researchers reported that increasing levels of a certain key protein protected successfully against cell death in both genetic and sporadic forms of the disease. Further, treating this pathway may also have implications for frontotemporal dementia because many of the same proteins are involved.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a debilitating neurodegenerative disorder that leads to paralysis and death due to the loss of motor neurons in the brain and spinal cord.

A central aspect of ALS is an accumulation of the protein TDP43, too much of which is toxic to cells. In the study, published in the journal PNAS, the researchers identified another protein, hUPF1, that keeps TDP43 in check, preventing cell death.

Nonsense Mediated Decay

First author Sami Barmada, MD, PhD, an assistant professor of neurology at the University of Michigan Medical School, said:

“TDP43 is a ‘Goldilocks’ protein: too much, or too little, can cause cellular damage. Over 90% of ALS cases exhibit TDP43-based pathology, so developing a treatment that keeps protein levels just right is imperative.”

Earlier studies had identified hUPF1 as a potential therapeutic target for ALS, but it was unclear how this protein prevented cell death.

In the current study, the scientists investigated hUPF1’s ability to protect against neurodegeneration using a cellular model of ALS. They discovered that genetically increasing levels of hUPF1 extended neuron survival by 50-60%.

Looking deeper, the researchers revealed that hUPF1 acts through a cellular surveillance system called nonsense mediated decay, or NMD, to keep TDP43 levels stable and enhance neuronal survival.

NMD monitors messenger RNA (mRNA). If a piece of mRNA is found to be defective, it is destroyed so that it cannot go on to produce dysfunctional proteins that can harm the cell.

It now appears that NMD also helps control the levels of proteins, like TDP43, that bind to RNA and regulate splicing. Since hUPF1 is a master regulator of NMD, altering it has a trickle-down effect on TDP43 and other related proteins.

“Cells have developed a really elegant way to maintain homeostasis and protect themselves from faulty proteins,” says senior author Steven Finkbeiner, MD, PhD, of 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.”

The next step would be to develop a drug that can target NMD, by manipulating hUPF1 or through other proteins that affect this system, to influence levels of TDP43 and protect neurons.


Sami J. Barmada, Shulin Ju, Arpana Arjun, Anthony Batarse, Hilary C. Archbold, Daniel Peisach, Xingli Li, Yuxi Zhang, Elizabeth M. H. Tank, Haiyan Qiu, Eric J. Huang, Dagmar Ringe, Gregory A. Petsko, and Steven Finkbeiner
Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1
PNAS June 8, 2015, doi: 10.1073/pnas.1509744112


“Amyotrophic lateral sclerosis (ALS) is a devastating disorder inevitably resulting in paralysis and death. Mutations in genes encoding RNA binding proteins cause familial ALS, but wild-type (WT) versions of these proteins accumulate in sporadic disease. In this study, we identified and characterized human up-frameshift protein 1 (hUPF1) as a potent modifier of neurodegeneration in ALS models.

hUPF1 dramatically reduced toxicity in primary mammalian neurons expressing WT and disease-associated mutant RNA binding proteins, demonstrating efficacy in familial and sporadic disease models, and verifying the existence of a conserved neurotoxic pathway targeted by hUPF1. The work has fundamental implications for ALS disease mechanisms and offers a novel perspective on effective therapies generalizable to both sporadic and familial disease.”

Photo: a computer-enhanced analysis of a 2D protein gel. The separated proteins form part of the brain mitochondrial proteome from a transgenic mouse carrying a mutation in the gene that encodes the enzyme Cu, Zn superoxide dismutase. Mutations in the SOD1 gene are responsible for some of the familial cases of amyotrophic lateral sclerosis, a type of motor neurone disease. Nicoletta Baloyianni, Wellcome Images