Shedding Light on Protein Related Diseases

Dartmouth researchers have found that some proteins turn into liquid droplets on the way to becoming toxic solids implicated in neurodegenerative diseases and other genetic disorders.

The findings, along with a series of related studies by scientists at other institutions, appear in the journal Molecular Cell.

The Dartmouth researchers studied proteins that have a massive expansion of a single amino acid, glutamine, typically associated with toxic protein solids. For example, neurodegenerative-linked proteins such as those in Huntington’s disease have these amino acids, which makes the protein sticky. The researchers found that proteins like this undergo a transition into liquid droplets on the way to becoming toxic, fibrous solids. These liquid droplets are similar to the ones made when oil and vinegar are mixed to make salad dressing. The researchers suspect that cells use this liquid state for normal physiology, but under certain conditions the proteins transition again from liquid to toxic solids. These kinds of droplets have also been called “membrane-free” organelles because they lack a barrier and are highly dynamic unlike many organelles such as mitochondria or nuclei.

“We found that RNA, the molecule traditionally thought as the intermediate between DNA and protein, has a potent role in driving the formation of the liquid states,” says senior author Amy Gladfelter, an associate professor of biological sciences. “They can drive the formation of droplets and give distinct physical properties to the droplets, which we think is important for how they are spatially arranged and function in the cell. It’s exciting that this is an example of RNA encoding physical properties of these compartments or drops rather than just encoding proteins.”

Image shows a DNA double helix.
The results are important because the human genome is filled with proteins that have similar sequences and almost all understanding of these proteins so far has focused on pathological states. Image is for illustrative purposes only.

The results are important because the human genome is filled with proteins that have similar sequences and almost all understanding of these proteins so far has focused on pathological states.

“Our work, along with the other recent papers, find a form of these proteins that is relevant to normal cell function and yet takes advantage of the very sequences that are linked to diseases for their normal functions,” Gladfelter says. “This type of mechanistic understanding of the protein’s normal function is critical for understanding and treating a myriad of diseases linked to protein aggregation.”

About this genetics and neurology research

Source: John Cramer – Dartmouth College
Image Source: The image is in the public domain
Original Research: Abstract for “RNA Controls PolyQ Protein Phase Transitions” by Huaiying Zhang, Shana Elbaum-Garfinkle, Erin M. Langdon, Nicole Taylor, Patricia Occhipinti, Andrew A. Bridges, Clifford P. Brangwynne, and Amy S. Gladfelter in Molecular Cell. Published online September 17 2015 doi:10.1016/j.molcel.2015.09.017


Abstract

RNA Controls PolyQ Protein Phase Transitions

Highlights
•RNA drives phase transition of Whi3, an RNA-binding protein with a long polyQ tract
•RNA alters Whi3 droplet viscosity, dynamics, and their propensity to fuse
•Different target mRNAs drive Whi3 to form droplets with distinct properties
•Whi3 droplets mature and appear fibrillar over time

Summary
Compartmentalization in cells is central to the spatial and temporal control of biochemistry. In addition to membrane-bound organelles, membrane-less compartments form partitions in cells. Increasing evidence suggests that these compartments assemble through liquid-liquid phase separation. However, the spatiotemporal control of their assembly, and how they maintain distinct functional and physical identities, is poorly understood. We have previously shown an RNA-binding protein with a polyQ-expansion called Whi3 is essential for the spatial patterning of cyclin and formin transcripts in cytosol. Here, we show that specific mRNAs that are known physiological targets of Whi3 drive phase separation. mRNA can alter the viscosity of droplets, their propensity to fuse, and the exchange rates of components with bulk solution. Different mRNAs impart distinct biophysical properties of droplets, indicating mRNA can bring individuality to assemblies. Our findings suggest that mRNAs can encode not only genetic information but also the biophysical properties of phase-separated compartments.

“RNA Controls PolyQ Protein Phase Transitions” by Huaiying Zhang, Shana Elbaum-Garfinkle, Erin M. Langdon, Nicole Taylor, Patricia Occhipinti, Andrew A. Bridges, Clifford P. Brangwynne, and Amy S. Gladfelter in Molecular Cell. Published online September 17 2015 doi:10.1016/j.molcel.2015.09.017

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  1. This process can definitely be induced by therapeutic treatment with amphetamines. I suspect it is related to CART, which can alter transcription factors. I know this because every time i begin another course of Vyvanse or Adderall, my blood becomes sticky and gooey and elastic. I also get abnormal deposits of a waxy lipoprotein? substance inside my hair follicles, over the entire area of my skin, including my face.In inflamed follicles, there is a pinkish gel-like substance, which also often contains debris. These follicles create horrible indurated lesions that will not heal until i have cleaned and debrided the lesion to remove the goo and debris. My scalp develops folliculitis (as does my skin) and in those follicles, a soft, sticky, gooey substance builds up.

    This may largely be due also to my having a chronic, years -long undiagnosed and hence untreated infection with Aeromonas Hydrophila. It was cultured from a sputum sample so it is certainly in my blood. It is also in my GI tract and God only knows where else.

    I have been very, very sick for over four years. Due to the current practice in medicine in this country, I have never received a diagnosis; worse, I have never had any attempt at diagnosis beyond routine CBC and CHEM 12. I begged for a sputum culture when I began having hemoptysis. When the results came back, the infection was minimized and I was advised only to continue the “symptomatic relief” provided by amphetamines.

    I am aghast at all this. I do live in a small town but I assumed any doctor who was unfamiliar with a bacteria would educate himself on its virulence and appropriate treatment. However, the diagnosis and treatment of illness and disease has fallen victim to the alteranate practice of symptom management. When I asked my doctor how abd why this could be, be became extremely angry with me and dismissed as a patient on the spot.

    So now I am critically ill and the only thing propping up enough to keep myself clean and fed are drugs that make me much sicker in the long term.

    Sorry to get off track. I only meant to offer some insight into possible associated factors in this pathological state. Perhaps you might have some suggestion or advice as to mitigation of this process or as to where treatment of this kind of disorder would best be obtained.

    My sincere gratitude to you for this article. My mother died of Alzheimer’s disease. The scarring of my skin is bad enough; I don’t want to die from a protein metabolism disease like she did.

    Sincerely,

    Marsha Owens

  2. A dam is near breaking releasing a flood of understanding key to many unsolved mysteries. Apparent spooky action at a distance can result from pH micro variations or supporting flow rates of metabolites or production rates of proteins. Not spooky, but dynamic action.

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