Snapshot: What is CRISPR?

A common nuisance for bacteria is the bacteriophage: a virus that uses the internal machinery of a bacteria to replicate its own genetic material. Bacteriophages do this by latching onto bacteria and injecting their DNA into the cell. As the cell grows and divides, the bacteriophage’s hope is that their genetic material is replicated alongside the bacteria’s own genome. Unfortunately for bacteriophages, many bacteria have evolved a method to fight off their attacks. After recognizing a viral infection, the bacteria integrate portions of the injected viral DNA into their own genome. The area where these viral DNA segments end up is known as the CRISPR sequence (short for clustered regularly interspaced short palindromic repeat). The viral DNA segments that were integrated into the CRISPR sequence are then replicated and attached to a bacterial protein called Cas9 (CRISPR-associated protein 9). These CRISPR-Cas9 pairs patrol the cell, acting as the bacteria’s antiviral immune system. If the same viral infection happens again, the DNA in one of the CRISP-Cas9 pairs will match part of the injected viral DNA and bind to it. Once bound, Cas9 cuts the viral DNA, which is then destroyed.

a DNA molelcule that has a fragment cut out of it. Scientific drawing and scribble are faint in the background
Artist’s cartoon of DNA that has been cut by CRISPR. Image courtesy of the NIH.

Recently, scientists have found a way to harness this system for manipulating genes (a process broadly called genetic engineering). By making an artificial CRISPR sequence, attaching that sequence to Cas9, then introducing the man-made CRISPR-Cas9 into a cell, it becomes possible to make a targeted cut in any gene. Making a CRISPR-Cas9 pair that targets one specific gene is as simple as making a CRISPR sequence that matches that gene.

Unlike in bacteria, most organisms repair rather than simply destroy cut DNA. This leaves the targeted genetic sequence available for further manipulation, including the introduction of a short mutation or even the insertion of a whole new DNA sequence. In essence, using the CRISPR-Cas9 system, scientists are now able to edit genes in a simple, targeted way.

CRISPR-Cas9 has become quite popular as a genetic tool in research settings: as of now, the genomes of anything from worms and fruit flies to mice and monkeys have been altered using this technique. While its use in humans is still in its early stages – the first patient treated using CRISPR began therapy earlier this year – is plausible that CRISPR-Cas9 could prove useful in altering the genomes of patients with genetic disorders (like, for instance, the SCAs). For patients, this might sound like a miracle cure. However, it is important to note that several concerns remain as to the ethics of human genetic engineering – the concept of “designer babies” being one of them.

If you’re interested in reading more about the conversation around CRISPR and bioethics, check out the articles by NPR and the National Human Genome Research Institute.

Snapshot written by Logan Morrison and edited by Dr. Maxime W. Rousseaux.

1 Year Anniversary of SCAsource!

SCAsource launched one year ago today on September 27, 2018. In that time we’ve had over 18,000 views and published over 40 articles. Now we are launching a survey about the website to make sure we are meeting our goals.

SCAsource is turning a year old! A huge thank you to all our volunteer writers, editors, and proofreaders who help make the content that gets posted every week. We couldn’t do this without them. Also a big thank you to all who read and share SCAsource content. You all are the reason we made SCAsource in the first place.

Here at SCAsource, we are so excited with how we have grown in these first twelve months, and can’t wait to see where we go from here. To get a better idea of if we are meeting our goals and how we can improve, we are launching a survey about SCAsource.

SCAsource reader survey logo, which is a clipboard that has a box with the checkmark in it
Introducing the SCAsource reader survey!

What is the SCAsource Reader Survey?

This study will look at the impact of SCAsource on its readers and their knowledge of research being conducted on spinocerebellar ataxias. For this study, you are invited to complete a brief online survey that will take about 20 minutes to complete.

Why are you doing a survey?

We want to check if SCAsource is achieving its goal of making ataxia research more accessible and understandable to readers. We will use this survey data to help improve future SCAsource content. Also, we hope by studying SCAsource, that we can provide a framework that other rare disease groups can use to launch their own websites.

Additionally, we want to use this data to show the impact SCAsource to potential sponsors and funders. We want to secure funding to cover the costs of keeping the SCAsource website online.

Are there any risks? Can I withdraw part of the way through the survey?

The risks involved in participating in this study are minimal. You do not need to answer questions that make you uncomfortable. If you decide to be part of the study, you can stop (withdraw) from the study at any point before submitting your survey responses. Once you have submitted your responses for this anonymous survey, your answers will be put into a database and will not be identifiable to you. This means that once you have submitted your survey, your responses cannot be withdrawn from the study because we will not be able to identify which responses are yours.

Where can I get more information about the SCAsource Reader Survey?

You can read the Study Letter of Information, which gives you the full details about the survey. This study has been reviewed and cleared by the Hamilton Integrated Research Ethics Board (HiREB).  If you have any concerns or questions about your rights as a participant or about the way the study is being conducted, call the Office of the Chair, HiREB, at 905.521.2100 x 42013.

Where can I fill out the survey?

Thank you in advance for your time and consideration with the SCAsource Reader Survey! You can access the survey online at this link. With your feedback, we look forward to making SCAsource even better!

International Ataxia Awareness Day 2019

Today marks International Ataxia Awareness Day (IAAD), 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. For more information on how you can participate in IAAD this year, take a look at the National Ataxia Foundation’s event page.

group of people, including some wheelchair users, stand in a circle holding their hands up. They are happy. Overtop is the IAAD2019 logo and website. www.ataxia.org
Image courtesy of the NAF.

Here at SCAsource, we are celebrating IAAD 2019 by highlighting our top ten most-read articles from this year. We hope you enjoy reading these throwbacks!

10. Decreasing ATXN3 levels can alleviate some symptoms in an SCA3 mouse model

Antisense oligonucleotides: a potential treatment for SCA3 that partially rescues SCA3 disease mouse models.

9. The Discovery of SCA8

How one team uncovered the first SCA known to be caused by a CTG repeat expansion mutation.

8. Approaching the age of clinical therapy for spinocerebellar ataxia type 1

New research (published Nov. 2018) reveals promising potential genetic therapy for SCA1.

7. Protein kinase C to the Rescue in Spinocerebellar Ataxias

Protein kinase C: one protein that may help to protect against cerebellar neuronal dysfunction & death in spinocerebellar ataxias.

6. Early Cerebellum Development Abnormality in Adult-Onset Spinocerebellar Ataxia Type 1

Researchers for the first time identified that spinocerebellar ataxia type 1 (SCA1) may have roots in early cerebellar circuit malfunction.

5. Snapshot: What are Clinical Trials?

Ever wonder what clinical trial “phases” mean? Why do trials need so many phases? How does this help test how safe a new treatment is? Here’s a quick overview of how drugs get from an idea in a research lab to market.

4. Dynamic duo strikes again – Orr and Zoghbi discover the primary driver of SCA1 pathology in the cerebellum

Research group uncovers the key molecular interaction that causes spinocerebellar ataxia type 1 (SCA1).

3. ASOs clear toxic protein from cells, reducing ataxia in SCA2 mice

Scientists uncover a promising therapeutic avenue to treat spinocerebellar ataxia type 2 (SCA2).

2. A novel therapeutic approach for the treatment of SCA3 

Researchers in the Netherlands uncover a new way to treat SCA3.

And last, but certainly not least:

1. Accidental discovery reveals possible link between cerebellar function and motivation

Stanford researchers accidentally discover a new role (reward prediction) for the cerebellum, the primary brain region affected by spinocerebellar ataxias.

logo of IAAD2019: a globe with multiple people from around the world marked on it

Non-invasive imaging of neurodegeneration in live animals

Written by Dr. Marija Cvetanovic   Edited by Larissa Nitschke

Purkinje cells (a type of neuron in the cerebellum) are the most vulnerable cells in many Spinocerebellar Ataxias (SCAs). While animal models of SCA have been very fruitful in understanding the mechanisms of Purkinje cell neurodegeneration, none of these models have allowed for visualization of neurodegenerative processes in live animals as the disease progresses – until now. In the laboratory of Dr. Reinhard Köster, researchers have developed a zebrafish model of SCA that allows for the expression of SCA-causing mutant protein in Purkinje cells and proteins that can be used to monitor Purkinje cell changes. As zebrafish larvae are almost transparent, researchers can now study pathogenic changes in neurons in a live animal during disease progression.

Since the 1993 discovery of the mutation that causes Spinocerebellar Ataxia Type 1 (SCA1), we have significantly increased our understanding of disease pathogenesis using animal models. While there are advantages and disadvantages of using any model, most researchers would agree that the similarity between humans and the animal used, plus the cost of creating and caring for the animals, are critical determinants of which model to choose. Mouse models, for instance, are useful to study pathogenesis at the molecular, cellular, tissue and behavioral level, but are costly to house and maintain. Fruit fly models, on the other hand, allow high-throughput studies (that is, studies that can produce a lot of relevant data quickly) of disease modifying properties but are much farther from human beings evolutionarily. Unfortunately, neither of these animal models allow us to follow up changes in neurons in the same animal throughout disease progression – to study the neurons, the animal must be euthanized and the brain must be dissected. Understanding how neurons are affected during disease progression, however, is very important. Observing the same neurons over time could increase our understanding of disease processes and inform us about the optimal timing for therapies. For example, if we were to identify changes in neurons that occur just prior to the onset of motor symptoms, this might mean that these changes are a contributing factor to behavioral pathology. This could also tell us the stage at which neurons start dying and disease thus becomes irreversible.

In an effort to examine how cells behave over time, many researchers use zebrafish. The fact that zebrafish embryos (larvae) are mostly transparent means that we can follow changes in neurons throughout disease progression. Moreover, in most SCAs, Purkinje cells in the cerebellum are the neurons that are most affected by the disease-causing mutant protein, and the zebrafish cerebellum has an anatomy and function that is quite similar to the human cerebellum. Zebrafish are also inexpensive and produce hundreds of offspring weekly, providing researchers with a large number of animals to study.

A dozen zebrafish swim in deep blue water. Zebra fish are narrow and long. They have two to three black stripes running down their side.
A school of Zebrafish (Photo by Lynn Ketchum, courtesy of Oregon State University)

Using state-of-the-art genetic approaches, Dr. Reinhard Köster’s laboratory at the Technical University of Braunschweig in Germany created a zebrafish model of SCA that expresses two types of protein in their Purkinje cells: a disease-causing SCA mutant protein, and a fluorescent reporter protein to monitor degenerative changes and cell death.

Continue reading “Non-invasive imaging of neurodegeneration in live animals”

Brain-derived neurotrophic factor: A new (old) hope for the treatment of SCA1

Written by Eviatar Fields Edited by Dr. Vitaliy Bondar

Scientists use Brain Derived Neurotrophic Factor to delay motor symptom onset and cell death in a mouse model of Spinocerebellar Ataxia Type 1

Spinocerebellar ataxia type 1 (SCA1) is a rare neurodegenerative disease that affects about 2 out of 100,000 individuals. Patients with SCA1 present with motor symptoms such as disordered walking, poor motor coordination and balance problems by their mid-thirties and will progressively get worse symptoms over the next two decades. No treatments for SCA1 exists. These motor symptoms cause a significant decrease in patient independence and quality of life. Scientists use mouse models that recreate many SCA1 symptoms to understand the cause of this disease and test new treatments.

In this paper, Mellesmoen and colleagues use a mouse model of SCA1 which presents with severe motor symptoms by adulthood. In order to measure the severity of the motor problems in the SCA1 mouse model, the researchers use a test called a rotarod. The rotarod test is similar to a rolling log balance: mice are placed on a rotating drum that slowly accelerates. Mice that can stay on the drum for longer durations have better motor coordination than mice who fall off the drum earlier. Mellesmoen was trying to find a way to get the mice to stay on the drum for longer.

artistic cartoon of male doctor sin from of a microscope and large DNA model
Cartoon of a medical researcher holding a clipboard. 

Purkinje cells, the main cells of the cerebellum, eventually die in SCA1 mouse models and in patients later in life. However, it remains unclear how and why these brain cells, which are responsible for the fine-tuning of movement and motor coordination, die. This is an important question as its answer might lead to new treatments that prevent brain cells from dying which might improve SCA1 symptoms. One possibility is that some changes in gene expression (that is, how “active” or “inactive” a gene is) causes the cells to die in SCA1 mice. To test this hypothesis, the authors used a technique called RNA-seq to examine how gene expression is altered in SCA1 mice compared to healthy mice.

Continue reading “Brain-derived neurotrophic factor: A new (old) hope for the treatment of SCA1”