Snapshot: What is Cerebrospinal Fluid (CSF)?

Public transit may not be the first thing that comes to mind when we think about the brain, but it’s a great way to understand how all the parts of the central nervous system work together. Nutrients, hormones, and other important molecules (the passengers) need to get on and off at different stations to do their work. They might first stop at the large internal chambers within the brain, called ventricles. From the ventricles, they can get to the central canal in the spinal cord, as well as the subarachnoid space. The subarachnoid space is a space between two membranes that surround the brain and spinal cord. It provides a stable structure for a network of veins and arteries.

The passengers are shuttled from station to station by the cerebrospinal fluid (CSF), a clear, colourless fluid that provides the central nervous system with necessary nutrients and hormones while carrying away waste products. CSF also cushions the brain and spinal cord by circulating between layers of tissues surrounding them. The whole public transit system is enclosed: the subarachnoid space and the ventricles are connected to the central canal in the spinal cord, forming a single reservoir for CSF.

Cerebrospinal fluid written in colorful letters under a Stethoscope on wooden background
Photo used under license by Sohel Parvez Haque/

CSF is made by the choroid plexus, a collection of tiny blood vessels called capillaries. Capillaries filter the blood and secrete it into the ventricles. When the pressure of CSF is less than the pressure in the capillaries, CSF flows out and into the ventricles. When the pressure of CSF is greater than that of the bloodstream, the extra fluid is absorbed from the subarachnoid space and into sinuses (large areas filled with blood), where it can flow into the surrounding veins. The blood supply in the central nervous system tightly regulates the movement of molecules or cells between the blood and brain. This blood-brain barrier is crucial for protecting the brain from toxins and pathogens. Dysfunction of this specific system contributes to the development of neurological diseases.

Anatomical labeled scheme with human head and inside of skull, including superior sigittal sinus, ventricles, arachnoid Villi and spinal cord central canal.
Structure of the ventricles and central canal components that contribute to the public transit system. Photo used under license by VectorMine/

Why is CSF Important for Neurodegenerative Diseases?

In neurodegenerative diseases like Spinocerebellar Ataxias, CSF contains molecules that can be used as biomarkers. Biomarkers are disease-specific proteins that change in concentration depending on disease stages. Biomarkers provide information on disease progression, with or without the impact of therapeutics. They are also crucial for understanding how disease processes work and assist in developing treatments.

The development of intrathecal injections, injecting into the central canal for distribution to the central nervous system (for example, spinal anesthesia), has been monumental for administering drugs in neurodegenerative diseases. In other words, not only can the public transit system of the central nervous system be investigated to see what passengers are associated with the disease, but it can be used to deliver “medicine passengers” to the place where the disease occurs.

If you would like to learn more about Cerebrospinal Fluid, take a look at these resources by MedlinePlus and WebMD.

Snapshot written by Kaitlyn Neuman and edited by Dr. Tamara Maiuri.

El tratamiento para la SCA1 no causa efectos secundarios no deseados en un modelo de ratón

Escrito por el Dr. Ronald Buijsen Editado por la Dra. Larissa Nitschke. Publicado inicialmente en el 28 de Enero de 2021. Traducción al español fueron hechas por FEDAES y Carlos Barba.

O’Callaghan y sus colegas muestran que los enfoques terapéuticos novedosos para reducir la proteína que causa la enfermedad en SCA1 no aumentan el riesgo de desarrollar cáncer o enfermedad de Alzheimer en ratones SCA1.

Las personas afectadas con ataxia espinocerebelosa tipo 1 o SCA1 llevan una expansión de un tramo repetitiva de ADN en el ATXN1 gen. La expandido ATXN1 gen codifica una proteína expandido ataxina-1, que se acumula y causa toxicidad en el cerebro. Esto provoca problemas de coordinación motora y letalidad prematura. Hasta ahora, no existe ningún tratamiento que ralentice, detenga o revierta la progresión de la enfermedad SCA1.

Aún así, varios estudios preclínicos demostraron que la reducción de los niveles de proteína ataxina-1 puede mejorar los déficits de coordinación motora en modelos de ratón SCA1. Una estrategia para reducir los niveles de ataxina-1 es el uso de oligonucleótidos antisentido (ASO) . Estos tratamientos de ASO escinden específicamente el ARNm de Atxn1 y reducen los niveles de proteína ataxina-1.

Este estudio, publicado por el grupo del Dr. Harry Orr en 2018 , mostró que la inyección de ASO en el cerebro de ratones SCA1 mejora los déficits motores, prolonga la supervivencia y revierte las anomalías neuroquímicas. Sin embargo, la reducción de los niveles de la proteína ataxina-1 podría provocar una expresión alterada de otras proteínas en el cerebro. Esto podría afectar la seguridad de esta estrategia de tratamiento. Por lo tanto, este estudio de seguimiento investigó si la reducción de los niveles de proteína ataxina-1 produce efectos no deseados.

a brown laboratory mouse sits in a researcher's gloved hand
El tratamiento con ASO para reducir los niveles de ataxina-1 no causa efectos secundarios no deseados en un modelo de ratón SCA1. La Imagen fue obtenida de Rama de Wikimedia.
Continue reading “El tratamiento para la SCA1 no causa efectos secundarios no deseados en un modelo de ratón”

ASO treatment to lower ataxin-1 levels doesn’t cause unwanted side effects in a SCA1 mouse model

Written by Dr. Ronald Buijsen Edited by Dr. Larissa Nitschke

O’Callaghan and colleagues show that novel therapeutic approaches to reduce the disease-causing protein in SCA1 do not increase the risk of developing cancer or Alzheimer’s disease in SCA1 mice.

People affected with Spinocerebellar Ataxia type 1 or SCA1 carry an expansion of a repetitive stretch of DNA in the ATXN1 gene. The expanded ATXN1 gene encodes an expanded ataxin-1 protein, which accumulates and causes toxicity in the brain. This causes motor coordination problems and premature lethality. So far, there is no treatment that slows, stops, or reverses SCA1 disease progression.

Still, several preclinical studies demonstrated that reducing ataxin-1 protein levels can improve the motor coordination deficits in SCA1 mouse models. One strategy to reduce ataxin-1 levels is the use of antisense oligonucleotides (ASO). These ASO treatments specifically cleave Atxn1 mRNA and lower ataxin-1 protein levels.

This study, published by the group of Dr. Harry Orr in 2018, showed that injection of ASOs into the brain of SCA1 mice improves motor deficits, prolonged survival, and reversed neurochemical abnormalities. However, lowering ataxin-1 protein levels might lead to altered expression of other proteins in the brain. This could impact the safety of this treatment strategy. Therefore, this follow-up study investigated whether lowering of ataxin-1 protein levels results in unwanted effects.

a brown laboratory mouse sits in a researcher's gloved hand
ASO research in SCA1 is promising. But before moving forward, more safety testing had to be done in SCA1 mouse models. Image courtesy of Rama on Wikimedia.
Continue reading “ASO treatment to lower ataxin-1 levels doesn’t cause unwanted side effects in a SCA1 mouse model”

2 minuti di Scienza: Cosa sono I nucleotidi antisenso?

I nucleotidi anti-senso (anche noti come ASOs o AON, dall’inglese Antisense oligonucleotides) sono piccole molecole che possono essere usate per prevenire o alterare la produzione di proteine. Le proteine sono la forza lavoro della cellula, e dirigono la maggior parte dei processi cellulari. Le proteine sono prodotte in due fasi: nella prima un gene che codifica per una proteina viene convertito in una molecola che contiene specifiche istruzioni, l’RNA messaggero (mRNA). L’ mRNA trasferisce l’informazione contenuta nei geni al compartimento che assembla le proteine. Qui, l’mRNA è infine trasformato in proteina. Gli ASOs sono corte sequenze di DNA a singolo filamento, complementari alla sequenza di uno specifico mRNA. In base a diversi tipi di modifiche chimiche della loro sequenza, gli ASOs possono determinare due tipi di effetti sull’ mRNA complementare. Alcune modifiche fanno si che gli ASO distruggano l’mRNA e, di conseguenza, causano la perdita della proteina corrispondente. Altre modifiche, invece, permettono agli ASO di mascherare certi tratti dell’mRNA bersaglio, causando la produzione di una versione alterata della proteina.

Come funzionano gli ASO nel corpo umano. Autore della figura Larissa Nitschke, creato con BioRender.

La maggior parte delle Atassie spinocerebellari (dall’inglese Spinocerebellar Ataxias, SCAs) sono causate dall’accumulazione di una proteina tossica in una specifica regione del cervello. Per questo motivo, il principale obiettivo del trattamento delle SCAs con gli ASOs è inibire la produzione della proteina tossica. Un esempio di questa applicazione degli ASO è il lavoro del Prof. Harry Orr all’ Università del Minnesota. Il suo gruppo di ricerca studia l’Atassia spinocerebellare di tipo 1 (SCA1), causata dall’accumulo tossico della proteina Ataxina-1. Iniezioni di ASOs in modelli animali di SCA1 riducono i livelli di Ataxina-1 e migliorano l’incoordinazione motoria tipica della SCA1. Un altro modo di usare gli ASOs per il trattamento delle SCAs è la modifica dell’informazione trasmessa dall’mRNA per produrre una versione alterata della proteina. Questo approccio è stato testato nel caso della Atassia spinocerebellare di tipo 3 (SCA3), nella quale un’espansione nel gene Atxn3 rende la proteina Ataxina 3 tossica. Il gruppo del Dr. van Roon-Mom, in Olanda, per esempio, ha usato gli ASOs per rimuovere esclusivamente la porzione espansa della proteina Atxn3, lasciando intatta il resto della struttura proteica e la sua funzione.

Entrambi gli studi, così come altri studi portati avanti per altre SCAs, hanno evidenziato il potenziale uso degli ASOs come strumenti terapeutici per le SCAs. Mentre la ricerca sugli ASOs per le SCAs è per lo più nella fase preclinica, il trattamento con gli ASO per altre malattie, come la Distrofia Muscolare di Duchenne e l’atrofia muscolare spinale, è stato già approvato dall’ente statunitense Food and Drug Administration. Ulteriori studi clinici saranno necessari per misurare il beneficio terapeutico degli ASOs in pazienti di SCAs.

Per saperne di più sugli oligonucleotidi antisenso, leggi questo articolo alla pagina  HDBuzz sugli ASOs in via di sviluppo per la malattia di Huntington.

“2 minuti di Scienza” scritto da Dr. Larissa Nitschke, revisionato da Dr. Hayley McLoughli, tradotto in italiano da Dr. Antonia De Maio. Pubblicato per la prima volta il 31 Maggio 2019.

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