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?”

Snapshot: What are Intrathecal Injections?

Drug delivery into the body can be achieved in several ways, from applying a medicated cream on the skin, to swallowing a pill, to injecting into a muscle or vein. Each route of delivery should at least achieve one thing – getting the drug to the part of the body where it can be helpful. Delivering therapeutic drugs into the brain, however, can be more difficult. Intrathecal injections are used to overcome this challenge.

Cartoon drawing of a woman's back, her hand resting on her lower back.
How do you get drugs to the brain? Through the back!

When a drug enters the body, it travels through the bloodstream until it reaches the target organs. But when a drug is destined to reach the brain, it needs to pass through a unique security feature known as the blood-brain barrier. The blood-brain barrier is important for keeping harmful and unknown substances out of the brain. It turns out that the majority of drugs injected into the body cannot pass this barrier. This poses a challenge for researchers and doctors for delivering important drug treatments to the brain.

One way that drugs can be delivered to the brain via the blood is by modifying their chemical nature slightly. This can help with entry through the blood-brain barrier. A more straightforward route of delivery is by injecting drugs into the brain space directly. Your brain inside your head and spinal cord along your back are bathed in and float in a liquid called cerebrospinal fluid (CSF).

CSF is a clear, colourless fluid that protects the brain from injury by absorbing shock, and it helps bring waste products out of the brain. Importantly, as CSF flows, it helps distribute substances around the brain. Injecting a drug directly in the CSF allows that drug to bypass the blood-brain barrier. One of the less invasive ways to access the CSF space is via injection through the thecal sac, the cushiony layer containing CSF that surrounds the spinal cord. This type of injection is therefore known as an “intrathecal injection”.

Intrathecal injections are injected into the cerebrospinal fluid around the spinal cord around the thacal sac (mid-back area). The injected drug then travels up the back to the brain.
A diagram of how intrathecal injections work. Image by Claudia Hung.

Intrathecal injections can be very helpful. They are used during surgeries to manage pain (spinal anaesthesia) and to deliver chemotherapeutic agents to target brain cancers. Intrathecal injections becoming an increasingly important route of administration for drugs investigated in neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, ALS, spinal muscular atrophy (SMA), and spinocerebellar ataxias (SCAs). These drugs include antisense oligonucleotides that can be delivered directly to the brain.

However, there are still a few challenges in giving medication through intrathecal injections:

  • Medication delivered by intrathecal injections may need to be given quite often. Since the CSF is replenished regularly, the substances are cleared quickly out of the brain and spinal cavity.
  • Intrathecal injections involve a needle being inserted into the spine. So they are more invasive and painful than a typical shot or swallowing a pill. This is especially true if multiple injections are needed.

Therefore, researchers and doctors are constantly trying to learn more about how drugs enter the brain. By studying this, they will make improvements in how medication is delivered to patients. Despite these challenges though, intrathecal injections are a clever and important way for delivering critical drugs to the brain to treat a wide range of diseases.

If you would like to learn more about intrathecal injections, take a look at these resources by the Allina Health and Cancer Research UK.

Snapshot written by Claudia Hung and edited by Judit M. Pérez Ortiz

Snapshot: What is the Blood-Brain Barrier?

What is the blood-brain barrier?

Blood circulates throughout the body in tubes called blood vessels, delivering oxygen and essential nutrients to different organs. However, not all things that circulate through the body can get into the brain. The blood vessels of the brain are slightly different. Their walls have a unique barrier that allows entry of some substances, but keeps others out of the brain. This unique security feature is known as the blood-brain barrier. This barrier allows passage of some substances, but can block out others. This is important because this provides access to substances that the brain needs to function, while keeping harmful substances at bay. The blood-brain barrier is therefore an important feature that keeps our brains and bodies healthy.

A crossing guard holds a stop sign with a brain on it in one hand. The other hand is held out to say "stop".
The blood-brain barrier is like a crossing guard. It helps some chemicals enter the brain, but it keeps others out.

How does the blood-brain barrier work?

The blood-brain barrier is the result of the coordinated effort of several players working together at a microscopic level. These players form physical and functional barriers to select what can enter or exit the brain. Like other blood vessels in the rest of the body, blood vessels in the brain are lined with a thin wall of cells called endothelial cells. Between these endothelial cells, there are gaps that can allow substances to exit the blood to the various organs in the body. However, in the brain, these cells form tight connections between the gaps to restrict large molecules from passing through.

Additionally, brain cells called astrocytes and pericytes wrap around endothelial cells to more strictly block what substances can get through. Very small molecules, such as hormones, can slip through this complex wall. Larger molecules, such as sugars, water, amino acids, and insulin, require help from proteins known as transporters to get through, and are a critical component of the blood-brain barrier.

What happens if the blood-brain barrier is not working properly?

Infections, abnormal inflammation, or prolonged stress in the body can contribute to larger gaps between the tight connections of the blood-brain barrier, seen in diseases such as multiple sclerosis or Alzheimer’s disease or with brain tumours. If the blood-brain barrier is not working properly, harmful substances that are usually kept out of the brain may enter and cause problems, and can start a harmful cycle of more infections and more inflammation.

What challenge does the blood-brain barrier post for brain therapies?

The blood-brain barrier is critical for regulating what enters or exits the brain to maintain a healthy brain. However, the blood-brain barrier also poses a challenge for researchers. Many potentially life-saving drugs developed for treating brain diseases and brain injury cannot pass through this barrier. To overcome this, scientists have devised novel ways to directly or indirectly deliver drugs into the brain. The therapeutic potential of smaller sized drugs (often called “small molecules”) is intentionally being tested as they can more easily pass from the blood to the brain.

Another alternative is making previously impenetrable drugs better at entering the blood-brain barrier. Scientists are trying to do this by attaching chemical modifications that “escort” them into the brain. Finally, direct access to the brain is created by injections that allow access to the brain space. We will talk more about this topic in our Snapshot on Intrathecal Injections next week!

If you would like to learn more about blood-brain barrier, take a look at these resources by the BrainFacts.org or The University of Queensland.

Snapshot written by Claudia Hung and edited by Judit M. Pérez Ortiz

Targeting protein degradation to alleviate symptoms in MJD

Written by Ambika Tewari   Edited by Brenda Toscano Márquez

Trehalose, a natural autophagy inducer shows promise as a therapeutic candidate for MJD/SCA3

Every cell has an elaborate set of surveillance mechanisms to ensure optimal functioning. As proteins are synthesized, errors can occur leading to misfolded proteins. These abnormal proteins can be harmful to the cell. For this reasons it is important to monitortheir occurrence and decide whether they should be degraded.  Autophagy is one way that these misfolded proteins can be degraded. Autophagy literally means self-eating and serves as a quality control mechanism. Defects in autophagy have been linked to several neurodegenerative disorders.

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 is caused by an abnormal expanded CAG repeat in the ATXN3 gene. This CAG expansion causes misfolding of the ataxin-3 protein. The now unstable ataxin-3 is prone to forming aggregates in cells of some regions of the brain including the cerebellum, brainstem and basal ganglia. The accumulation of ataxin-3 in the cell leads to the progressive loss of neurons in the affected brain regions.

Normal ataxin-1 proteins becomes misfolded due to CAG expansion, but autophagy with proteins LC3B and Beclin-1 should degrade and break down misfolded ataxin-3
A diagram of how autophagy should break down abnormal expanded ataxin-3. But what happens when this break down doesn’t happen? Diagram by  Ambika Tewari using BioRender.

Researchers, eager to help patients with MJD, began to question why would the cellular surveillance system allow this toxic accumulation of misfolded ataxin-3. Surely there are mechanisms, like autophagy, to prevent this from occurring. This led to a number of studies that found that autophagy is defective in MJD patients. This was also confirmed in different mouse and cell models of MJD. In fact, earlier studies by the lab of Dr. Luís Pereira de Almeida found that increasing the amount of an autophagy protein (beclin-1) in the brain of an MJD mouse model improved some of the behavioral and neuropathological deficits. Together, these studies have provided evidence that autophagy may serve as a therapeutic target for MJD.

Continue reading “Targeting protein degradation to alleviate symptoms in MJD”