Trapping pathological proteins that cause many neurodegenerative disorders
, short for trans-activation response DNA-binding protein 43, is a versatile DNA and RNA binding protein that functions in intracellular RNA transcription, alternative splicing, and regulation of mRNA stability. RNA is responsible for transporting instructions from DNA to protein-building machines for protein production. In general, TDP-43 acts as an RNA chaperone in cells. It binds to RNA, directs its processing, transports it to the desired location and adjusts it so that other proteins are properly expressed.
Early studies have shown that TDP-43 is abundantly accumulated in neurons and glial cells in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and produces cytotoxicity, leading to neuronal degeneration and death, thus resulting in motor dysfunction, dementia and even death of patients. It is also a sign of neurological diseases such as Alzheimer's disease, Parkinson's disease and Huntington's.
One characteristic of TDP-43 is its inherent tendency to aggregate. A previous study found that the interaction of TDP-43 molecules and the resulting concentration depend on a small helical portion of the C-terminal domain of the protein, called helix.
Recently, researchers at the University of Pittsburgh have discovered a way to trap TDP-43 so that it does not form toxic masses that cause neurodegeneration.
In their study published in Neuron, they described how to reconstruct the pathology of TDP-43 in the laboratory, and how oligonucleotides can save the aggregated neurons of TDP-43. Oligonucleotides are a short RNA strand that mimics the natural protective mechanism of cells.
The researchers considered that most people with the neurodegenerative disease do not have specific mutations, so they target not the genes that cause the disease in some patients, but the proteins that accumulate in almost all patients. This has never happened before.
The first step was that the research team had to replicate the pathology of TDP-43 in the cultural human cells, so-called a disease in a dish. To achieve the aim, they developed a system that uses light pulses to push TDP-43 proteins together into toxic pellets. This method is very effective to see cells dying in front of their eyes.
After a closer look, the team found that this technique works only in the absence of a TDP-43 RNA binding partner. These RNA binding partners are locked together with the TDP-43 protein to prevent them from forming plaques. And this is why normal cells are protected from the buildup of toxic TDP-43.
Based on the natural defensive mechanism, the researchers created a TDP-43 targeting oligonucleotide that imitates the role of its RNA binding partner. And they called it the 'bait-oligonucleotide'. It is like that when you fish, you will use bait to catch fishes. Differently, they left the lure to capture the extra proteins to stop them from coagulating together.
To their inspiring, the oligonucleotide successfully traps TDP-43 protein to prevent its accumulation, thus preventing cell death.
And then they believed that the same approach can also be applied to other proteins for their neurotoxic clumps, such as Tau in Alzheimer's disease and alpha-synuclein
in Parkinson's disease. They may also have natural "bait" available.
However, they point out that any treatment developed in a dish must be tested in animal and human clinical trials before it can be widely used.
Their oligonucleotides are not the first oligonucleotides to undergo this process. One such drug, targeting a gene mutation behind spinal muscular atrophy, is on the market, and two other drugs for ALS are in clinical trials. Their oligonucleotide will be the first method to directly target protein aggregation, which has the potential to help many people.
Cite this article
CUSABIO team. Trapping pathological proteins that cause many neurodegenerative disorders. https://www.cusabio.com/c-20857.html