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ALS Alert Newsletter

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Oct 11
2016

Have Proteins, Will Travel

New study shows that toxic proteins linked to C9orf72 can travel between neurons

One of the lingering mysteries in ALS research is understanding how the disease spreads from one motor neuron to another. In a new study in Cell Reports, a team of researchers led by Davide Trotti, a neuroscientist at the Jefferson Weinberg ALS Center, in the Vickie and Jack Farber Institute for Neuroscience at Thomas Jefferson University, and Piera Pasinelli, science director of the Packard Center, have identified one potential mechanism. They showed that small toxic proteins called dipeptide repeats (DPRs), produced as a byproduct of the C9orf72 repeat expansion, can travel between neurons and other brain cells called glia.

Piera Pasinelli and Davide Trotti lead a team of researchers at the Vickie and Jack Farber Institute for Neuroscience at Thomas Jefferson University. (Photo credit: Thomas Jefferson University)

Many neurodegenerative diseases, including ALS, Alzheimer’s, and Parkinson’s, are characterized by the buildup of misfolded proteins. Research in Alzheimer’s disease has shown that some of these misfolded proteins have the potential to spread from cell to cell throughout the nervous system in a process called seeding. The proteins spread from one nearby cell to another, although they can occasionally travel to cells that are further away. Although researchers have studied this process in Alzheimer’s disease, there has been much less work in ALS.

Scientists have long linked the misfolding of proteins like SOD1 and TDP43 to ALS, but the more recent discovery of the C9orf72 mutation, in which a sequence of six DNA bases is repeated hundreds or thousands of times, has identified a new type of toxic protein. The large number of repeats confuses the cellular machinery that turns DNA into protein. As a result, the cell accidentally transcribes the DNA sequence in the repeat, creating DPRs.

A clump of toxic DPR protein (white) in an affected neuron.

Given that toxic proteins linked to other neurodegenerative diseases could move between cells, Trotti and colleagues wanted to investigate whether this might be the case for the ALS-linked DPRs as well. The researchers used artificially synthesized DPRs attached to a small fluorescent tag, and found that the proteins could travel between motor neuron-like cells and mature cortical neurons. They also showed that the DPRs could travel from mature cortical neurons to a type of glial cell called an astrocyte, which provides structural and metabolic support to neurons. Other experiments revealed that the toxic proteins could travel to both upstream and downstream neurons.

Knowing that proteins could travel was an important step, but the scientists also wanted to know how the proteins were able to move. In other neurodegenerative diseases, researchers had shown that harmful proteins could be released from the cell when it died, by a process called exocytosis. When this happens, a small piece of the cell membrane, filled with proteins and other material, pinches off from the cell. The exosome can travel to other cells and fuse with the host membrane, depositing its contents inside.

Dipeptide repeat (DPR) proteins can move from cell to cell in several different ways, including to the neuron immediately up or downstream, or via small vesicles called exosomes.

Using both cultured primary cortical neurons and spinal motor neurons derived from induced pluripotent stem cells from patients with ALS, the researchers showed that the DPRs could be transmitted from neuron to neuron both by exosome-dependent and exosome-independent methods.

The results, Trotti stressed, are still at an initial phase.

“They need to be studied more using animal models. There’s a strong probability that we will see a similar thing in these models. If that’s so, we can work on finding ways to stop cell to cell transmission of these proteins and create an additional therapeutic target,” he said.