Snapshot: What are Purkinje cells?

Purkinje cells are important neuronal cells located in the outer layers of the cerebellum. The cerebellum is part of the brain that is primarily known for controlling sense of balance and movement but can also influence learning, memory, and mood.

Purkinje cells receive lots of information from other neurons through their large and highly branched processes called dendrites (Figure 1, see below). This information is processed in large oval cell bodies of Purkinje neurons and is transmitted from Purkinje neurons through their axons, another type of neuronal process, to other neurons residing deep within the cerebellum.

Left, drawing of purkinje neuron. Right, image of a tree
Figure 1. Drawing of Purkinje cell by Spanish scientist Ramon y Cajal illustrating large and beautiful dendrites (bottom of dendrite labeled with d, top labeled by arrow) and axon (labeled with a). Information flows from top to bottom in this image, where Purkinje neurons receive input in the dendrites, process it in the cell body, and transmit it to other neurons through the axon (a). Photo of tree is on the right for comparison.

Purkinje cells look a lot like trees. The dendrites are like the leaves and branches, the cell body is like the tree trunk, and the axon is like the roots. Information starts at the top and goes to the bottom. This information processing ensures balance and accuracy of movements.

Because of these important roles, dysfunction or loss of Purkinje cells often leads to problems with balance and movement. Indeed, a loss of normal Purkinje neuron function appears to be very important for the development of ataxia.

Many researchers study different inherited ataxias by expressing mutant proteins in Purkinje cells in mouse models of these diseases. For example, the first mouse model created for spinocerebellar ataxia type 1 (SCA1), called ATXN1[82Q], expresses mutant Ataxin-1 only in Purkinje neurons. These mice develop balance and movement deficits and were critical for increasing our understanding of how Purkinje neurons influence how SCA1 progresses.

If you would like to learn more about Purkinje cells, take a look at this Encyclopaedia Britannica article.

Snapshot written by Dr. Marija Cvetanovic, edited by Dr. David Bushart

 

 

Hunting for a needle in a haystack: Scientists identify the gene that causes ARSACS

Written by Dr. Sriram Jayabal Edited by Dr. Brenda Toscano-Marquez

Scientists uncover SACS, a gene containing the largest exon identified in vertebrates, which leads to ARSACS when mutated.

What is your morning routine? Coffee first, right? Now, try to think of all the diverse movements you need to make to accomplish this routine. For instance, just to get a cup of coffee, you have to complete a sequence of motor tasks: you start by pulling the pot out of the machine, then you walk to the tap, fill the pot with water, walk back, pour the water into the machine, put your coffee in, and then finally turn on the machine.

needle in haystack
Picture courtesy of Pixabay

To perform any of these movements, your brain needs to communicate with dozens of muscles in your body. Unfortunately, in people who are affected by hereditary ataxias, the brain loses the ability to coordinate these precise movements. These diseases primarily affect the way patients walk (the symptom that defines “ataxia”), eventually forcing them to use a wheelchair for the rest of their lives.

Hereditary ataxias can be broadly classified as either dominant or recessive. Dominantly-inherited ataxias can be passed down even if only one of the parents is affected; therefore, the disease does not skip generations. Recessive ataxias are inherited from parents who are both carriers of the disease mutation (and who do not usually show any symptoms). Therefore, recessive ataxias can skip generations.

One such recessive ataxia is called Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS). It was first discovered in people from the Charlevoix-Saguenay-Lac-Saint-Jean region of Quebec, Canada [1]. In this region, it is estimated that one out of every 22 individuals is a carrier for the disease mutation [2]. Though prevalent in this specific area of Canada, ARSACS has now been identified all across the world. Symptoms usually start in early childhood when toddlers are learning to walk. These children experience stiffness in the legs (spasticity) and incoordination in their gait (ataxia), leading them to fall more often. They also have difficulties writing, speaking, and performing tasks that require manual dexterity (usually actions that involve hand movements, like reaching for and grasping an object). They continue to experience worsening gait as they age, often needing a cane or handrail to move around by the time they reach adolescence. Around this time, many patients also experience retinal hypermyelination (an eye abnormality) and peripheral neuropathy (damage to the nerves throughout the body). By their thirties, they become dependent on a wheelchair. There is currently no cure for ARSACS, so it is imperative to study this disease’s underlying causes to identify effective treatments.

Continue reading “Hunting for a needle in a haystack: Scientists identify the gene that causes ARSACS”

SCAsource Turns 6 Months Old!

Today marks the six-month anniversary of the SCAsource website launch. A big thank you to all who have read our posts and have come back for more! It is really exciting to see SCAsource grow from an idea shared between colleagues to an actual website that people read.

chocolate cupcake with "Happy Anniversary" topper in front to sign which says "Happy Six Month Anniversary SCAsource!"
Celebratory cupcake purchased to mark the six month anniversary of the SCAsource website. It was very delicious.

Another thank you to all our volunteers who help to write, edit, and proofread content for the site. SCAsource wouldn’t be possible without your help.

We are looking forward to seeing how SCAsource continues to grow over the next few months and years. Today though, we are excited to celebrate what we have done and are happy to announce a brand-new type of article we will be testing out.

Over the past few months, we’ve had some messages from readers asking us specific questions such as: What is DNA? What are clinical trials? What are Purkinje cells? Inspired by these questions, we are excited to announce SCAsource Snapshots.

SCAsource Snapshot logo with a camera "snapping" a picture
The new logo of SCAsource Snapshots

Snapshots are short entries on a single scientific concept or topic. They’ll explain what a topic is and how it ties into ataxia research. We have 12 topics lined up based on your suggestions to try out this new style. Snapshots will be uploaded every other week starting next Friday, April 5. Please let us know what you think!

Approaching the age of clinical therapy for spinocerebellar ataxia type 1

Written by Dr. Marija Cvetanovic Edited by Dr. Maxime W. Rousseaux

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

A research team comprised of scientists from academia and industry have tested a new treatment for Spinocerebellar ataxia type 1 (SCA1), bringing disease-modifying therapy one step closer to the clinic. SCA1 is a dominantly-inherited ataxia that is currently untreatable. Symptoms of the disease include progressive loss of balance, slurring of speech, difficulties with swallowing and coughing, mild cognitive impairments, and depression. With a life expectancy after diagnosis of only 10-15 years, SCA1 is one of the fastest-progressing SCAs: after symptoms first appear, patients typically have just over a decade before these symptoms become so severe that they cause death (often due to respiratory failure). In 1993, collaborative efforts from the laboratories of Drs. Harry T. Orr and Huda Y. Zoghbi discovered that SCA1 is caused by the expansion of a CAG repeat somewhere in a patient’s DNA. CAG repeats cause a polyglutamine expansion in the protein that the mutated gene encodes; in this case, the group later identified that this had occurred in Ataxin-1 (ATXN1), the gene that encodes the ATXN1 protein. The SCA1 mouse models that Drs. Orr and Zoghbi generated (and graciously shared with the scientific community) have allowed for significant advances in the understanding of SCA1 pathogenesis over the years. Now, they provide preclinical evidence of a promising therapy to alter the progressive motor deficits and fatal outcome of SCA1.

stethoscope on top of laptop
Photo by Pixabay on Pexels.com

Continue reading “Approaching the age of clinical therapy for spinocerebellar ataxia type 1”

Spinocerebellar Ataxia Type 1 is Caused by a Trinucleotide DNA Repeat

Written by Hillary Handler  Edited by Dr. David Bushart

How researchers found that SCA1 is caused by an expanded, repetitive DNA sequence – a discovery that has allowed for accurate SCA1 diagnosis and more focused research strategies

Before the true genetic basis of Spinocerebellar Ataxia Type 1 (SCA1) was discovered, researchers and medical doctors noticed that SCA1 causes motor dysfunction, death of specific types of brain cells, and premature death in affected patients. By assessing health outcomes in multiple families affected by SCA1, scientists also recognized that the disease is inherited in an autosomal dominant manner. This means that each person with an SCA1 diagnosis has a 50% chance of passing the disease to each of his or her children. In addition, researchers noticed that affected members of SCA1 families displayed a disease feature called anticipation: a trend of increasing symptom severity and earlier age-of-onset as the disease is passed from generation to generation. Despite these discoveries, the specific genetic mutation responsible for causing SCA1 had not yet been identified or described. Determining the genetic cause of an inherited disease is critical for allowing accurate diagnosis of the condition. Furthermore, understanding the genetics of SCA1 would provide researchers with important clues about disease pathology that could help with designing and developing treatments.

Researcher looking through a microscope
Photo by Pixabay on Pexels.com

 

One of the groups that sought to identify the specific genetic cause of SCA1 was led by Dr. Harry Orr. These researchers published their findings in a landmark 1993 paper (Nature Genetics, 1993), which described the process by which they made their discovery. First, a technique called “linkage analysis” was used to determine the general location of the SCA1 gene within the human genome. By tracking how SCA1 is inherited relative to other, well-characterized genetic locations, the team was able to narrow their search to a small portion of chromosome 6’s short arm known as region 6p22-6p23. The researchers also noted that anticipation is often indicative of a particular DNA feature known as a trinucleotide repeat. To determine if a trinucleotide repeat was indeed causing SCA1, these scientists used DNA cloning and screening techniques within the identified region of chromosome 6. These experiments identified a CAG trinucleotide repeat within the SCA1 genomic target region of DNA.

Continue reading “Spinocerebellar Ataxia Type 1 is Caused by a Trinucleotide DNA Repeat”