Tangles of misfolded proteins underly a family of related neurological disorders including Alzheimer’s disease. Previous approaches toward the prevention or removal of such tangled proteins have often involved understanding and modifying the body’s immune response toward such detritus. In a new study, scientists found that restoring levels of mRNA expression from affected model cells resulted in a decrease in protein tangles. This result suggests that protein tangles may eventually be dissolved or targeted for removal through the addition of exogenous RNA or through increased translation of relevant genetic material within the cell.
A hallmark of some more well-known neurological diseases is the presence of unusual clusters
of protein that are seen in specific parts of the brain when autopsy tissue is visualized as a slice on a slide under a microscope.
Image: Unfolding the role of protein misfolding in neurodegenerative diseases. C. Soto, Nature Reviews Neuroscience volume 4, pages 49–60 (2003) DOI: 10.1038/nrn1007
Until now, scientists and physicians have largely considered the protein tangles as garbage that the body is having trouble removing.
While normal versions of such proteins may contribute to protein tangles, alternate variants of the gene encoding these proteins (alleles) invariably exist within in a large population. Some variants have amino acid substitutions that are well known to cause or contribute to the protein misfolding that enhances the accumulation of toxic aggregates. It has typically been hypothesized that the variant amino acids that exist in these alternate versions of the proteins cause the misfolding and subsequent clinical effects of misfolded tangles.
The current work suggests however that rather than being the result of something that itself has gone wrong, protein tangles may instead be caused by some smaller component of the larger overall system that has declined over time on aging and is now preventing movement—a key that unlocks a compartment door or some grease that allows the protein to untangle. In this scenario, intervention at a point seemingly distant and unrelated to the protein tangle itself may be the thing that needs attention. If we can figure out what the thing is that is missing from the puzzle, it may be much easier than we realized to help the tangles degrade more naturally and go about their merry way.
Image; When fast is better: protein folding fundamentals and mechanisms from ultrafast approaches. Victor Muñoz, Michele Cerminara, Biochemical Journal Aug 30, 2016, 473 (17) 2545-2559; DOI: 10.1042/BCJ20160107
While it is normal, extremely common and necessary for life that proteins can form clusters, clumps, and tangles, these features become problematic if embedded as a structural or functional cell component that then make them difficult to remove. Given the added separation the brain requires from the rest of the body for somewhat obvious reasons of safety, the need to carry out the cellular trash is especially problematic for neurons. When this system goes awry, it can be a major contributing factor toward symptoms associated with diseases including Parkinson’s and Alzheimer’s.
Given the complex and often overlapping roles that any one given protein can play in the human body, it has been especially tricky to try and understand what went wrong and how we might fix it when they are seen in such diseased conditions. Proteins that can arrange themselves into long strands of repeating units may make a very useful cytoskeleton, able to shuttle interior components about the cell or arrange its parts in space within a larger organ.
Less obvious is their ability and need to be broken down and used for food or signaling purposes when the brain becomes starved for sugar or is otherwise in need of specific metabolic intermediates.
One of the primary responsibilities of proteins is to grab and hold on to other things that the body needs. Much of the food we eat for example is broken down into smaller pieces in the digestive tract. These pieces cross the stomach lining and enter the blood stream where they are transported and directed toward where they are needed most, through the binding and action of an extremely abundant serum protein called albumin. Proteins can provide such an ideal transport medium due to the areas they naturally possess where things that are oilier can congregate hidden away from the otherwise water-soluble blood stream. Other small and mobile proteins found in the body are well known for latching on to and transporting items such as drugs, vitamins, metal ions such as sodium, potassium, and calcium, and oxygen.
Proteins also bind DNA found in the cell’s nucleus where they turn genes on and off and allow for the transcription of message into RNA and translation into those very proteins. In a recent report, scientists created a cellular model for the protein tangles found in neurological diseases that they could then manipulate at will to test for contributing factors. In doing so, they discovered that the nucleic acid RNA, similar in nature to DNA, seemed to maintain the protein in an un-clumped state, while a lack of RNA in a specific region of the cell promoted clumping.
This exciting finding suggests that small bits of RNA could act as a therapeutic agent in the prevention or reversal of protein clumps by dissolving them.
Alternate treatment strategies have focused on the use of antibodies, themselves proteins created by the immune system that can recognize and bind to neuronal tangles. The hope in these strategies is that the antibody will effectively tag the garbage and make it easier for the immune system to see, in the hopes that it can better toss it out. These approaches however are notorious for inducing unwanted and potentially very dangerous side effects. The use of RNA as a therapeutic agent should avoid much of these unwanted effects for reasons related to its ability, or rather lack thereof, to stimulate an immune attack against it. A small bit of engineered RNA might well be made then that can penetrate the blood brain barrier to reach the tangles without triggering an immune attack and subsequent damage from inflammation.
In summary,
"When your automobile stops working, I’d recommend checking the oil pump before replacing the engine. Just find me a better repair manual or a YouTube video for the brain and I’ll be fine! And if the maid needs to clean my room, I’d rather he try a key first before breaking down the door. Now where did I leave that wrench…"
-Robert L. Haining PhD
Great fleas have little fleas upon their backs to bite 'em,
And little fleas have lesser fleas, and so ad infinitum.
And the great fleas themselves, in turn, have greater fleas to go on;
While these again have greater still, and greater still, and so on.
(From Augustus De Morgan "A Budget of Paradoxes")
Edited for Style; Joy R Bunt
Graphical abstract from the currently reported-on story:
https://doi.org/10.1016/j.neuron.2019.01.048
Summary
TDP-43 proteinopathy is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia where cytoplasmic TDP-43 inclusions are observed within degenerating regions of patient postmortem tissue. The mechanism by which TDP-43 aggregates has remained elusive due to technological limitations, which prevent the analysis of specific TDP-43 interactions in live cells. We present an optogenetic approach to reliably induce TDP-43 proteinopathy under spatiotemporal control. We show that the formation of pathologically relevant inclusions is driven by aberrant interactions between low-complexity domains of TDP-43 that are antagonized by RNA binding. Although stress granules are hypothesized to be a conduit for seeding TDP-43 proteinopathy, we demonstrate pathological inclusions outside these RNA-rich structures. Furthermore, we show that aberrant phase transitions of cytoplasmic TDP-43 are neurotoxic and that treatment with oligonucleotides composed of TDP-43 target sequences prevent inclusions and rescue neurotoxicity. Collectively, these studies provide insight into the mechanisms that underlie TDP-43 proteinopathy and present a potential avenue for therapeutic intervention.
Source article I’d found to initiate my writing: https://www.pbs.org/wgbh/nova/article/protein-clumping-drives-als-and-dementia-new-method-could-prevent-it/?utm_source=FBPAGE&utm_medium=social&utm_term=20190306&utm_content=2165358465&utm_campaign=NOVA+Next&linkId=64194687&fbclid=IwAR02AovHcwnX6WQOtOC2KlxWkg6qnwUAg8Fye_4Mzt3VeuBK9iX81MH52cg