A New Key to HD? How TDP43 Might Spoil The Show
Like a movie editor removing bloopers, our cells also edit their protein machines to make films worth watching. New research finds the cell’s movie editor is distracted in Huntington’s disease.
A new study led by researchers from the University of California Irvine gives us new clues as to how genetic message molecules are edited differently in the context of Huntington’s disease (HD). Let’s get into what the scientists found and why this matters for our understanding of HD.
The cellular editor
When watching our favorite movies, we don’t typically consider the extraordinary amount of editing required to make them flow seamlessly from scene to scene. Behind this movie magic are editors who work tirelessly to enhance the drama of key plot twists with clever and precise cuts, removing unnecessary scenes and bloopers, and eventually stitching everything together to create the polished films we love.
Cells use a similar editing process when creating proteins, the molecular machines that perform nearly all the activities inside cells. Proteins are like polished feature-length films in theater and, just as movies originate from a collection of unedited scenes, proteins are also made from an unedited version called mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein..
mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. is a long string-like molecule with multiple “scenes” containing the genetic instructions needed to make protein. Through an important process called splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions., cells remove segments of mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. called introns (bloopers) and keep segments called exonsExons The small fraction of our DNA that is directly used to instruct cells how to make proteins (key plot twists). If everything runs smoothly, the initial unedited mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein., containing a mix of introns and exonsExons The small fraction of our DNA that is directly used to instruct cells how to make proteins, will have its introns removed leaving it with only exonsExons The small fraction of our DNA that is directly used to instruct cells how to make proteins when it is used to make proteins.
However, this editing process malfunctions in people with HD, leading to serious problems in how some of the protein machines work inside brain cells.
Cells with bloopers and missing scenes
“Splicing errors are harmful because a cell’s protein machines made from improperly spliced mRNA either function abnormally or fail to be produced altogether.”
Scientists have long suspected that mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. is disrupted in the brains of people with HD. Previous research has found introns mistakenly included in the final mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. molecule and exonsExons The small fraction of our DNA that is directly used to instruct cells how to make proteins mysteriously missing. This would be like publishing movies without removing bloopers and missing critical plot twists – not something cinema-goers would be happy with!
Recent experiments suggest that the protein encoded by the gene that causes HD, called Huntingtin (HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15), may play a key role in this confusion. HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 is an mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein.–binding protein and is known to interact with other proteins that also bind mRNA. This raises an interesting question: if splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. is disrupted in HD, HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 interacts with mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein., and HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 interacts with proteins involved in splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions., could mutant HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 be interfering with the cell’s mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. editing process?
Blockbuster bombs in the cell
Intrigued by this mystery, Dr. Leslie Thompson and her team at the University of California Irvine investigated the underlying cause of splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. errors. Using mouse models of HD and post-mortem human brains, they first confirmed that splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. is disrupted in the HD brain, discovering various types of mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. with undeleted introns (bloopers) and missing exonsExons The small fraction of our DNA that is directly used to instruct cells how to make proteins (key scenes). These errors were most common in the medium spiny neuronsneuron Brain cells that store and transmit information, the type of brain cell that is most vulnerable in HD. In addition, the mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. message molecules that were found to contain splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. errors were particularly important for activities like neural communication and brain development.
Image credit: MIKI Yoshihito
Splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. errors are harmful because a cell’s protein machines made from improperly spliced mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. either function abnormally or fail to be produced altogether. This would be like a movie so poorly edited that the publisher decides to pull it before hitting theaters.
These findings are exciting for HD researchers because they may explain why some proteins don’t work very well or are less abundant in HD cells, despite having no mutation or known interaction with HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15. Although the consequences of splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. errors are complex and difficult to predict, they are undoubtedly harmful to overall brain function.
TDP43: A distracted editor
Leslie and her team scrutinized the proteins interacting with HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 in search of possible causes of the splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. errors. They focused on proteins that, like HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15, also interact with mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. – like partners in crime.
“These findings are exciting for HD researchers because they may explain why some proteins don’t work very well or are less abundant in HD cells, despite having no mutation or known interaction with HTT.”
One protein, TDP43, stood out because it not only interacts with HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 and mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. but is also known as a kind of splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. editor-in-chief. TDP43 is an extensively studied protein because its mutation causes a different neurodegenerativeneurodegenerative A disease caused by progressive malfunctioning and death of brain cells (neurons) disease, Amyotrophic Lateral Sclerosis (ALS), so researchers already have a great profile on it. Adding to their suspicion, the types of mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. that TDP43 is known to edit closely overlap with the mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. containing splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. errors in HD.
Beginning their investigation of TDP43, Leslie and her team first tested if TDP43 binds to the same mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. that is spliced incorrectly in HD. Sure enough, they found that TDP43’s favorite mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. largely overlapped with the abnormally spliced mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. in HD. When researchers compared the splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. changes of cells missing TDP43 to cells containing mutant HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15, they observed remarkable similarities. This suggests that TDP43 dysfunction might be the root cause of splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. errors in HD.
How HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 spoils the show
The team hypothesized that HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15’s interaction with TDP43 could be “stealing” it from the studio, and preventing it from splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein.. To test this, they first confirmed that HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 interacts with TDP43 in mouse brains. Next, they examined brain cells from people with HD to see if TDP43 was in its normal location, the nucleusnucleus A part of the cell containing genes (DNA), where splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. occurs. Like an absent movie editor, TDP43 was mostly located outside of the nucleusnucleus A part of the cell containing genes (DNA), a clear indication that something was wrong.
Scientists have long recognized changes in TDP43 location from the nucleusnucleus A part of the cell containing genes (DNA) to the cytoplasmcytoplasm A part of a cell including everything inside the cell and outside the nucleus; where most of the cell's work happens (outside the nucleusnucleus A part of the cell containing genes (DNA)) as a hallmark of ALS, and this change in location is associated with errors in splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions.. What’s worse, the small amount of TDP43 still in the nucleusnucleus A part of the cell containing genes (DNA) appeared inactive because it was locked up in big protein clumps with HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15, like an editor buried by movie reels!
Another red flag the scientists noticed was the absence of special chemical markings on mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein., called m6A, that guide TDP43 to splice sites, like sticky notes reminding the editor to delete certain scenes. These chemical markings on mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. were significantly reduced in HD brains, particularly on mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. prone to splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. errors. Without these marks, TDP43 is unable to identify the “bloopers” it needs to remove and likely contributes to TDP43’s dysfunction.
At this point, the researcher’s working hypothesis was that mutant HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 abnormally interacts with TDP43, keeping it out of the nucleusnucleus A part of the cell containing genes (DNA) or trapping it in large clumps, distracting it from its splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. duties. On top of this, the sticky notes (m6A marks) that guide TDP43 to the bloopers (introns) were mostly missing in HD brains. Together, these issues prevent mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. from being properly edited, resulting in broken or missing protein machines. Over time, these problems lead to sick brain cells that can’t communicate properly.
Putting the editor back to work
Although the current study does not attempt to correct or reverse these splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. errors, its findings will help guide future therapeuticstherapeutics treatments. The involvement of TDP43 is particularly interesting because TDP43 is already extensively studied in ALS, and hundreds of TDP43-targeting therapies are currently in development. This does not necessarily mean treatments designed for TDP43 will work for HD, but they may serve as promising starting points for new therapeutic strategies or to help us better understand what TDP43 is doing in HD.
Future research is critical to understanding how mutant HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 disrupts TDP43 activity, and whether restoring TDP43 activity can correct the splicingsplicing the cutting up of RNA messages, to remove non-coding regions and join together coding regions. errors observed in HD. Like editing a movie, fixing these molecular errors could turn a blockbuster disaster into a beloved masterpiece we cherish for years to come.
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