New Drug Target to Treat ALS Identified

Revelations about a key cellular pathway have important implications for neurodegenerative diseases like ALS and frontotemporal dementia.

Scientists from the Gladstone Institutes and the University of Michigan have identified a cellular mechanism that can be targeted to treat ALS. The researchers revealed that increasing levels of a certain key protein successfully protected against cell death in both genetic and sporadic versions of the disease. What’s more, 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 primary feature of ALS is an accumulation of the protein TDP43, too much of which is toxic to cells. In the current study, published in the journal PNAS, the researchers identified another protein, hUPF1, that keeps TDP43 in check, thereby preventing cell death.

Blue is the nucleus, cyan is hUPF1, green is TDP43, red is the cell body in this image.
Blue is the nucleus, cyan is hUPF1, green is TDP43, red is the cell body in this image. Image credit: Sami Barmada.

“TDP43 is a ‘Goldilocks’ protein: too much, or too little, can cause cellular damage,” says first author Sami Barmada, MD, PhD, 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.”

Previous investigations 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 tested 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%. Digging 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.

This protective mechanism (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, 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.”

The scientists say the next step is 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.

About this neurology research

Scientists from the University of California San Francisco, Wright State University, Brandeis University, and Weill Cornell Medical College also took part in the research.

Funding: Funding was provided by the National Institutes of Neurological Disorders and Stroke, the Robert Packard Center for ALS Research, Target ALS, the Roddenberry Stem Cell Program, the Koret/Taube Center for Neurodegenerative Disease, and the Protein Folding Diseases Initiative at the University of Michigan.

Source: Dana Smith – Gladstone Institute
Image Credit: The image is credited to Sami Barmada
Original Research: Abstract for “Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1” by 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 in PNAS. Published online June 8 2015 doi:10.1073/pnas.1509744112


Abstract

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNA-binding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43- and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders.

“Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1” by 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 in PNAS. Published online June 8 2015 doi:10.1073/pnas.1509744112

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