The vast majority of people who develop the rare neurological disease amyotrophic lateral sclerosis have one feature in common: toxic buildup of faulty TDP-43 protein in the affected nerve cells.
Postmortem evidence suggests that 97 percent of people with amyotrophic lateral sclerosis (ALS) have these toxic protein deposits.
Now, scientists at the University of Pittsburgh in Pennsylvania have developed an approach that could prevent the formation of toxic TDP-43 deposits.
They recreated conditions that would lead to a buildup of TDP-43 followed by cell death in cultured human nerve cells.
At this point, they noticed that the deposits only formed when certain molecules that target TDP-43 — namely, the protein's RNA binding partners — were missing. Adding a molecule that could mimic the action of the missing RNA binding partners, however, prevented TDP-43 deposits from forming in the cells.
The study, which now features in the journal Neuron, is unique in that it focuses on proteins rather than genes.
"Instead," explains senior study author Christopher J. Donnelly, Ph.D., who is an assistant professor of neurobiology, "of targeting the gene that causes disease in a subset of patients, we're targeting the proteins that clump in nearly all of them."
"That's never been done before," he adds.
ALS lies on a 'neurodegenerative spectrum'
ALS, a progressive condition, causes the death of the nerve cells, or neurons, that control voluntary movement. The nerve cells that die include those that allow people to talk, walk, and chew.
According to the Centers for Disease Control and Prevention (CDC), due to incomplete records, it's not clear how many people in the United States have ALS.
However, where reports do exist, they suggest that "almost 16,000 people" had ALS in the U.S. in 2014, and about 5,000 people per year learn that they have the disease.
There is currently no cure for ALS, and there are no effective treatments that slow, stop, or reverse the progress of the condition. ALS can develop at any age, but it most commonly develops in people aged 55–75, and men are slightly more likely to develop it than women.
Most people live 2–5 years after symptoms start, although there are cases in which people survive longer. The renowned physicist and cosmologist Stephen Hawking, for instance, died 55 years after learning that he had developed ALS in 1963.
In their study background, Dr. Donnelly and colleagues note that because of a "[s]ignificant overlap of clinical, genetic, and neuropathological features," scientists have proposed that ALS and frontotemporal dementia lie at different points on the same "neurodegenerative disease spectrum."
New approach investigates proteins
They decided to investigate proteins instead of genes because, as Dr. Donnelly explains, "the vast majority of patients with neurodegenerative disorders do not have specific mutations." The time was ripe for an investigation of TDP-43 because, thanks to new technology, it was possible to observe the protein's interactions inside cells. This was not possible before.
The team used optogenetics, which is a new technology wherein scientists can use light beams to nudge molecules inside cells toward certain interactions.
They created ALS-like disease conditions in a dish and then observed what happened when they nudged the TDP-43 proteins toward each other.
The scientists watched as the human nerve cells died after TDP-43 proteins clumped together inside them.
Further investigation revealed that the proteins only formed toxic deposits in the absence of their RNA binding partners.
It seems that the RNA binding partners protect the nerve cells by attaching to the TDP-43 proteins and preventing them from clumping together.
'Bait-oligonucleotides' attached to proteins
Inspired by what they saw, the researchers developed an oligonucleotide molecule that specifically targets and attaches to TDP-43 like an RNA binding partner.
The approach worked: The team saw how the proteins did not form deposits in the presence of introduced oligonucleotides, and that the cells continued to live. Dr. Donnelly says that they nicknamed the molecules "bait-oligonucleotides."
He and his team believe that similar approaches using "disease in a dish" and "bait" molecules could work in other neurodegenerative disorders involving faulty proteins.
These include Alzheimer's disease, in which tangles of tau protein build up inside cells, and in Parkinson's disease, in which cells become clogged with deposits of a-synuclein protein.
However, there is still a lot of work to do to translate the promising results of the laboratory into a treatment that will work in humans.
"If you're fishing, you're trying to use bait to trap the fish. In our case, we're leaving the bait there for the extra protein to keep it from clumping together."
Christopher J. Donnelly, Ph.D.