Snapshot: What is Protein Degradation?

The Life Cycle of a Protein

No protein is made to last forever. Just as DNA and RNA direct a coordinated process for protein creation, there is also a process for proteins to be broken down by the cell. We call this proteolysis or protein degradation.

Proteins are broken down for a number of reasons. First and foremost, it’s a strategy for quality control. After a string of protein building blocks are put together, they are bent and folded into a  specific shape that allows the protein to interact with other proteins in a useful way. You can think of it like a daisy in a daisy chain- the stem needs to be carefully folded and tied or the daisy chain falls apart entirely. Cells have tools to identify misfolded proteins and break them down quickly to prevent problems.

Even beyond quality control, proteins have a certain lifespan within the cell. Regular protein recycling ensures that there is always an available supply of protein building blocks for the creation of new proteins. Removing older proteins also gives cells flexibility in terms of adjusting to environmental changes.

A bright blue plastic recycling bin.
Reuse and recycle. Protein degradation is how your cells break down old or broken proteins so their parts can be reused.
Continue reading “Snapshot: What is Protein Degradation?”

Mutated ataxin-1 protein forms harmful, doughnut-shaped aggregates that are not easily destroyed

Written by Brenda Toscano Marquez   Edited by Marija Cvetanovic

Insoluble clumps of mutated ataxin-1 capture essential proteins and trigger the creation of toxic reactive oxygen species.

All proteins produced by our cells consist of long chains of amino acids that are coiled and bent into a particular 3D structure. Changes in that structure can cause serious issues in a cell’s function, sometimes resulting in disease. Spinocerebellar ataxia type 1 (SCA1) is thought to be the result of one such structural change. The cause of SCA1 is a mutation that makes a repeating section of the ATXIN1 gene abnormally long. This repeated genetic code, “CAG,” is what encodes the amino acid glutamine in the resulting ataxin-1 protein. Therefore, in the cells of patients with SCA1, the Ataxin-1 protein is produced with an expanded string of glutamines, one after the other. This polyglutamine expansion makes the mutated ataxin-1 protein form clumps in many different types of cells – most notably, though, in the cells most affected in SCA1: the brain’s Purkinje cells.

Recent research suggests that these clumps, or “aggregates,” not only take up space in the cell, but that the act of ataxin-1 proteins clustering together might even be beneficial in early stages of disease (it’s possible that the proteins wreak less havoc when they’re in large clumps, rather than all floating around individually). However, another line of research suggests that ataxin-1 aggregates might also be toxic, triggering signals that lead to the cell’s death. As such, how exactly these aggregates affect the deterioration of cells has remained an important question in SCA1 research.

n a search for answers, an international team led by Stamatia Laidou designed a unique cell model of SCA1 to track the development of ataxin-1 aggregates. Their study, published in a recent paper, made use of normal human mesenchymal stem cells that had been engineered to make a modified version of the ataxin-1 protein. In these cells, ataxin-1 was produced not only with the SCA1-causing expansion, but also with a marker protein attached to its end. This marker, known as “green fluorescent protein” (GFP), is used extensively in biological research because it glows under fluorescent light.

doughnut with white and pink sprinkles
Laidou and colleagues have observed mutated ataxin-1 clumps that cause cell stress. Photo by Tim Gouw on Pexels.com

Using this to their advantage, Laidou and her team used a fluorescent microscope to follow the formation of ataxin-1 aggregates over the course of 10 days. The abnormal protein first started accumulating in the nucleus as small dots. As time went on, these dots started blending together, increasing in size. By ten days, the ataxin-1 aggregates had grown even more, forming a doughnut-shaped structure that occupied most of the cell’s nucleus – a crucial structure that houses the cell’s genetic information. These results were intriguing, since the accumulation of normal, non-expanded Ataxin-1 protein does not result in an aggregate with a doughnut shape.

Continue reading “Mutated ataxin-1 protein forms harmful, doughnut-shaped aggregates that are not easily destroyed”

International Ataxia Awareness Day 2020

logo of International Ataxia Awareness Day: a globe with multiple people from around the world marked on it
Image courtesy of the National Ataxia Foundation.

Today marks International Ataxia Awareness Day, which is celebrated every year on September 25th. IAAD brings people together from around the world to raise awareness about this group of rare diseases and to raise money for continuing research efforts.

Here at SCAsource, we are celebrating International Ataxia Awareness Day 2020 by highlighting our top ten most-read articles from this year. We hope you enjoy reading these throwbacks!

10. A New Use for Old Drugs

Basic biology helps identify a new treatment for ataxia. Work from groups in Michigan and California show in mice that not all medications that improve disease symptoms in the short term will continue to do so in the long term

9. How an ataxia gene increases the risk for Alzheimer’s disease

In a tour de force study, a collaborative team of scientists led by Dr. Rudolph Tanzi (Harvard Medical School) and Dr. Huda Zhogbi (Baylor College of Medicine) found a novel relationship between the Spinocerebellar ataxia type 1 gene (ATXN1) and Alzheimer’s disease.

8. A Potential Treatment for Universal Lowering of all Polyglutamine Disease Proteins

One drug to treat them all: an approach using RNA interference to selectively lower the amount of mutant protein in all polyglutamine diseases. Work by a group in Poland shows initial success in Huntington’s Disease, DRPLA, SCA3/MJD, and SCA7 patient cells.

7. A novel gene therapy-based approach with therapeutic potential in SCA3

Cholesterol to the rescue: An alternative approach to treating SCA type 3 using gene therapy.

6. Snapshot: What is Omaveloxolone?

A new therapeutic compound shows promise to treat Friedrich’s Ataxia. But what exactly does Omaveloxolone do in the body? What next steps are being taken to test it?

5. Byproducts of canola oil production show therapeutic potential for MJD and Parkinson’s Disease

Collaboration between researchers in Portugal and the United Kingdom discovers that a canola oil by-product shows promise, corrects MJD/SCA3 and Parkinson’s Disease symptoms in animal models.

4. Snapshot: The next-generation of CRISPR is prime editing – what you need to know

The CRISPR gene-editing toolbox expanded with the addition of prime editing. Prime editing has astounding potential for both basic biology research and for treating genetic diseases by theoretically correcting ~89% of known disease-causing mutations.

3. Two or more birds with one stone: Designing a single therapeutic strategy to treat multiple types of spinocerebellar ataxia

A newly-proposed treatment strategy might be effective against several forms of spinocerebellar ataxia and other CAG repeat-associated disorders

2. Sunrise of Gene Therapy for Friedreich’s Ataxia          

Researchers from the University of California show they can “edit” the Frataxin gene in human cells from Friedreich’s Ataxia and transplant them into mice. This lays the groundwork for this method to be tested for safety.

1. Gene Therapy Validated In Human SCA3 Stem Cells

A research group in Michigan report the creation of the first NIH-approved human cell model that mirrors SCA3 disease features – cellular defects that, after gene therapy, show improvement

Spotlight: The Neuro-D lab Leiden

Principal Investigator: Dr. Willeke van Roon-Mom

Location: Leiden University Medical Centre, Leiden, The Netherlands

Year Founded: 1995

What disease areas do you research?

What models and techniques do you use?

A group photo of members of the Neuro-D lab Leiden standing outside on a patio.
This is a group picture taken during our brainstorm day last June. From left to right: Boyd Kenkhuis, Elena Daoutsali, Tom Metz, Ronald Buijsen, Willeke van Roon-Mom (PI), David Parfitt, Hannah Bakels, Barry Pepers, Linda van der Graaf and Elsa Kuijper. Image courtesy of Ronald Buijsen.

Research Focus

What is your research about?

The Neuro-D research group studies how diseases develop and progress at the molecular level in several neurodegenerative diseases. They focus on diseases that have protein aggregation, where the disease proteins clump up into bundles in the brain and don’t work correctly.

We focus strongly on translational research, meaning we try to bridge the gap between research happening in the laboratory to what is happening in medical clinics. To do this we use more “traditional” research models like animal and cell models. But we also use donated patient tissues and induced pluripotent stem cell (iPSC) models, which is closer to what is seen in medical clinics.

Our aim is to unravel what is going wrong in these diseases, then discover and test potential novel drug targets and therapies.

One thing we are doing to work towards this goal is identifying biomarkers to measure how diseases progress over time. To do this, we use sequencing technology and other techniques to look at new and past data from patients.

Why do you do this research?

So far there are no therapies to stop the progression of ataxia. If we can understand what is happening in diseases in individual cells, we can develop therapies that can halt or maybe even reverse disease progression.

Identifying biomarkers is also important, because it will help us figure out the best time to treat patients when we eventually have a therapy to test.

Stylized logo for the Dutch Center for RNA Therapeutics
The Neuro-D lab Leiden is part of the Dutch Center for RNA Therapeutics, which focuses on RNA therapies like antisense oligonucleotides. Logo designed by Justus Kuijer (VormMorgen), as 29 year old patient with Duchenne muscular dystrophy.

Are you recruiting human participants for research?

Yes, we are! We are looking for participants for a SCA1 natural history study and biomarker study. More information can be found here. Please note that information about this study is only available in Dutch.

Fun Fact

All our fridges and freezers have funny names like walrus, seal, snow grouse and snowflake.

For More Information, check out the Neuro-D lab Leiden website!


Written by Dr. Ronald Buijsen, Edited by Celeste Suart

Fishing for a solution to SCA38 – are omega-3 fatty acids the key to symptom relief?

Written by Dr. Siddharth Nath Edited by Dr. Sriram Jayabal

SCA38 results in a deficiency of an omega-3-fatty acid called docosahexaenoic acid (DHA). Scientists from Italy had shown previously that short-term DHA supplementation reduces disease symptoms. Now, new research from the same group finds that this impact continues with long-term DHA supplementation.

What is SCA38?

One of the rarer forms of ataxia, SCA38 is an autosomal dominant SCA that occurs as a result of mutations in the ELOVL5 gene. This gene contains the recipe for the protein called elongase. It is responsible for building long-chain fatty acids in the brain, including docosahexaenoic acid (DHA), a process key for normal cellular function. Importantly, this protein is found mostly in Purkinje cells, a special type of neuron found within the cerebellum of the brain.

In SCA38, mutant elongase is found primarily in a part of the cell called the Golgi apparatus, which is responsible for packaging proteins and finalizing production, similar to a quality-control technician in an assembly line. Normally, elongase is found at the endoplasmic reticulum, which is further up the assembly line, more akin to the fabrication section.

This mislocation of the protein may explain why it is unable to produce sufficient amounts of long-chain fatty acids to support healthy Purkinje cell function. Deficiencies in DHA resulting from mutations in elongase are detectable by blood tests.

spilled bottle of yellow capsule pills
Photo by Pixabay on Pexels.com

Docosahexa-what?

You’ve probably heard of omega-3-fatty acids. Omega-3 fatty acids are part of a larger group of molecules called polyunsaturated fatty acids to which the omega-6 fatty acids also belong. DHA is a type of omega-3 fatty acid. Omega-3 fatty acids and omega-6 fatty acids are often touted as a key component of a healthy diet.

Omega-3-fatty acids are important building blocks of the cellular membrane, which is part of all cells in the body. Humans aren’t able to make omega-3-fatty acids ourselves, we need to get them from our diet. That is why many food guides have recommended intakes of omega-3 and omega-6 fatty acids from oily fish and nuts. Vegetarians can also supplement their diet with flaxseed or algae capsules to get these fatty acids in their diet.

DHA is just one of many omega-3-fatty acids and it is most prevalent in the membranes of brain cells, where it plays a key role in normal brain function. Thus, when there is a disturbance or deficiency in the level of DHA, we can expect brain function to become impaired, as is the case in SCA38.

Continue reading “Fishing for a solution to SCA38 – are omega-3 fatty acids the key to symptom relief?”