ALS Hallmark, Clumps of TDP-43 Protein, Appears to Protect Nerve Cells, Study Reports

ALS Hallmark, Clumps of TDP-43 Protein, Appears to Protect Nerve Cells, Study Reports

In contrast to what is often assumed, new research suggests that clumps of the protein TDP-43 — a hallmark of amyotrophic lateral sclerosis (ALS) — actually protect nerve cells rather than harm them.

If this finding confirmed in future studies, it could hugely impact how ALS and other neurodegenerative diseases are treated.

The study, “The mutational landscape of a prion-like domain,” appeared in the journal Nature Communications.

As with Alzheimer’s and Parkinson’s, protein aggregation (clumping) marks ALS. However, the presence of aggregates only weakly correlates with disease progression, and treatment approaches that have aimed to prevent or lessen clumping repeatedly fail to benefit people with Alzheimer’s or ALS.

Researchers with the Center of Genomic Regulation and the Institute of Bioengineering of Catalonia (IBEC) focused on TDP-43, a protein that normally stabilizes RNA molecules. When faulty, however, this protein aggregates inside nerve cells. Such clumping is typically seen in ALS, frontotemporal dementia, and inclusion body myositis.

Yet, whether TDP-43 becomes toxic to nerve cells because it aggregates, or if byproducts are at play, is “still very unclear and hotly debated,” the study notes.

Join the ALS forums: an online community especially for patients with Amyotrophic Lateral Sclerosis.

The scientists used an approach called systematic, or “deep,” mutagenesis to better understand the specific toxic types of TDP-43. “By studying all possible mutations in a protein, we have a much more reliable way to understand toxicity and we are excited to move on to many more proteins implicated in neurodegenerative diseases,” Benedetta Bolognesi, PhD, the study’s first author, said in a press release.

They induced more than 50,000 mutations — changing one or two amino acids, the building blocks of proteins — in the prion-like domain (PRD) of TDP-43. This protein region resembles that of infectious yeast prions, and is associated with the formation of liquid-like cellular condensates (liquid-like droplets within cells) and insoluble aggregates.

Analysis revealed that mutant proteins with increased hydrophobicity (naturally repelling water) and aggregation were less toxic in the yeast model. But mutant forms leading to liquid-like cellular condensates, most likely found around the nucleus, were more toxic than normal TDP-43.

“This is the exact opposite of what we expected,” said Ben Lehner, PhD, the study’s senior author and a professor at ICREA.

Data also showed that mutations had their strongest effects in a central “hotspot” region of 31 amino acids within the protein’s PRD, with mutations both strongly increasing and decreasing toxicity.

“Consistently, mutations that reduce hydrophobicity and the aggregation potential of TDP-43 increase the toxicity of the protein,” the investigators wrote. “Although they reduced the formation of large, solid aggregates, mutations that increase toxicity promote the formation of alternative … liquid-like TDP-43 condensates clustered at the nuclear periphery.”

They concluded: “We propose therefore that aggregation reduces the toxicity of TDP-43 to yeast cells because it titrates [adjusts the balance of] TDP-43 away from this toxic liquid-like phase … [and] propose that aggregation of TDP-43 is not harmful but actually protects cells.”

The team is now testing whether a similar protective effect can be seen in mammalian cells and nerve cells.

These results also led the researchers to suggest that treatments “promoting rather than alleviating aggregation might be the more appropriate therapeutic goal in neurodegenerative diseases.”

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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4 comments

  1. Jim Moore says:

    My wife has FTD/PPA caused by the mutation of the C9orf72 gene. Four male members of her family have died from ALS. Been following most of the current research and find it very compelling. God bless all of the researchers working on finding a cure for these horrible diseases.

  2. Dave Reckonin says:

    Well well well. A cellular activity that was thought to be damaging is now thought to be protective of neurons.
    What a crafty villain is ALS. He/it has sent thousands of researchers down the wrong path seeking ways to de-aggregate. It makes me wonder about the God we were all forced to believe in as impressionable children, who created the Universe and everything in it, has outsmarted researchers to maintain the elusiveness of a cure and continue the heartbreak.
    One very smart entity, that.

  3. Jane Erway says:

    I guess this will just give them more years of fooling around and coming up with nothing as people die. How much longer will this go on. I would think that trials should be going on and I see none. Why is that? Seems like it is not an expensive trial and money has been coming in since the water pail event. I want to know why there is no new medicine in 25 years, not five years, not ten but 25 years. Where has all that funding gone? Certainly not to those told to just go home and die and maybe someday a cure will come along. A cure should be here by now PERIOD!. I cannot even get a return call for an appointment for a second opinion. I don’t call this progress I call it the same old nothing. They throw out bones and then hide for another 10 years. Enough is enough, maybe time to fire half of these so called researchers doing nothing and put the money to one good facility where all can come together and share their ideas. But scattered all over, sharing nothing, each doing his/her own thing does not seem to be the answer. However, they make lucrative salaries don’t they??

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