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Jun 3
2020

New links between toxic protein and ALS discovered

ALS Headlines, Packard Center News
Neuroscientists at Thomas Jefferson University have identified a new way that repeat expansion in the C9orf72 gene—the most common genetic cause of ALS and FTD—can contribute to ALS.

In the years since scientists discovered the repeat expansion in the C9orf72 gene—the most common genetic cause of ALS and FTD—they have learned a lot about how it might cause disease. A new study in EMBO Molecular Medicine by Packard scientists Piera Pasinelli and Davide Trotti, neuroscientists at Thomas Jefferson University, has identified a new way that this repeat expansion can contribute to ALS. Their work showed how a small, toxic protein produced by the expansion can create problems at the neuronal synapse, and how these dysfunctions can potentially be fixed, which provides a new drug target.

One of the leading candidates for the expansion’s contribution to motor neuron toxicity are dipeptide repeats, produced when the cell’s protein-making machinery attempts to translate the expansion. Because the large number of repeats confuses the machinery, the DNA sequence can be ‘read’ forwards or backwards and from several different starting points. This results in small peptides of two amino acids, and the C9 repeat expansion produces five different ones. Two of these dipeptide repeat proteins (DPRs), known as GR and PR, are acutely toxic to motor neurons. Another, GA, is produced in the highest abundance and is also toxic, but in a slower, more chronic fashion.

Because of the lag time in the development of GA toxicity, Pasinelli and Trotti wanted to study how GA affected neurons with the hopes that it might provide clues about ways to slow or stop this process. Previous studies of the effects of GA in cells showed that neurons transfected with GA showed significant signs of dysfunction, leading to motor and cognitive deficits, but not increased cell death. This indicates a chance that they could be brought back from the brink with the right intervention. Finding the target of that intervention would mean uncovering precisely how GA damaged neurons.

The researchers started by trying to figure out how GA affected neuron signaling. Their work showed that GA peptides containing up to 400 repeats could be found in both the axons and dendrites of motor neurons differentiated from induced pluripotent stem cells derived from patients carrying the C9orf72 repeat expansion. The GA peptides can move within the neurons, but they don’t interfere with the movement of other molecules within the cells. Subsequent experiments show that the GA-induced motor neuron toxicity occurs at a later date, supporting the initial hypothesis that a window of time existed before GA becomes overtly toxic.

One of the results of this later-term toxicity is altered neuronal firing due to an increased influx of calcium ions after depolarization. Because dysfunctions in calcium homeostasis are known to cause dysfunctions at the synapse, the team led by Trotti and Pasinelli looked at whether proteins that release the tiny, neurotransmitter-filled bubble-like synaptic vesicles might be impacted. By transfecting wild-type motor neurons with GA peptides of various lengths, the researchers showed that larger GA peptides led to larger decreases in a synaptic vesicle protein called SV2. These levels were also reduced in iPSC-derived C9 motor neurons. The researchers found they could artificially increase SV2 levels in these motor neurons, and that this restored normal synaptic function.

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