Tag: SCA3

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

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”

Snapshot: What does dominant ataxia mean?

Ataxias can occur due to a multitude of reasons. One way a patient might acquire ataxia is from an accident or an injury – not as a result of genetics. On the other hand, a patient could also inherit a specific mutation (a genetic defect, in other words) from one or both of their parents. In this case, the ataxia is called “hereditary.” Hereditary ataxias can be further classified as either “dominant” or “recessive.”

What is a dominantly-inherited disorder?

Most genes in our body have two copies: one that we inherit from our mother, and one that we inherit from our father. Dominantly-inherited disorders are diseases in which a mutation in just one copy of a gene is enough to cause disease. When both copies of a gene need to be mutated to cause symptoms, the disorder is known as “recessive” (learn more in the Snapshot on recessive ataxias). For a patient with a dominantly-inherited ataxia, this means that there is a 1-in-2 chance that their children will inherit the disease-causing mutation (assuming that their spouse is unaffected). If both spouses are affected by the same dominantly-inherited disease, this chance increases to 3-in-4. In cases where the child inherits both mutant copies of the gene, the symptoms are often more severe than when a single copy is inherited.

Visual depiction of paragraph above
How dominant disorders are inherited. Illustration by Larissa Nitschke, created with BioRender.

Which ataxias are dominantly-inherited?

The most well-known ataxias with dominant inheritance patterns are the Spinocerebellar Ataxias (SCAs), such as SCA1, SCA2, SCA3, SCA6, and SCA7. Each disease is caused by defects in a different gene. Due to the high similarity in symptoms among all ataxias, genetic testing is often required to determine the exact gene mutation and type of ataxia a patient has.

How can a patient prevent passing on a dominantly-inherited disorder to their children?

There are multiple options to prevent passing on the disease to your child if you are affected by a hereditary ataxia. One potential option is to perform in vitro fertilization (IVF), a technology that is used the conceive embryos outside the human body. The embryos can be screened for genetic mutations, allowing only the healthy embryos to be implanted into the uterus.

If you are affected by a hereditary ataxia and want to prevent having a child with ataxia, it is recommended to talk to your physician and genetic counselor regarding reproductive options.

If you would like to learn more about in vitro fertilization and embryo screening, please take a look at these resources by the University of Pennsylvania. If you want to learn more about dominant ataxia, take a look at these resources by the National Organization for Rare Disorders and Ataxia Canada.

Snapshot written by Larissa Nitschke and edited by Dr. Marija Cvetanovic.

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

Written by Dr. Maria do Carmo Costa, Edited by Dr. Hayley McLoughlin

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

Isolated compounds or extracts (containing a mixture of compounds) from certain plants are showing promise as potential anti-aging drugs or as therapeutics for neurodegenerative diseases. Some of these plant compounds or extracts can improve the capacity of cells to fight oxidative stress that is defective in aging and in some neurodegenerative diseases. Machado-Joseph disease, also known as Spinocerebellar ataxia type 3, and Parkinson’s disease are two neurodegenerative diseases in which cells inability to defend against oxidative stress contributes to neuronal death. In this study, the groups of Dr. Thoo Lin and Dr. Maciel partnered to test the therapeutic potential of an extract from the canola plant rapeseed pomace (RSP) with antioxidant properties in Machado-Joseph disease and Parkinson’s disease worm (Caenorhabditis elegans) models.

Canola field with snowcapped mountains in the background, July 1990
Canola field with snowcapped mountains in the background, image courtesy of USDA NRCS Montana on Flickr.

Machado-Joseph disease is a dominant neurodegenerative ataxia caused by an expansion of CAG nucleotides in the ATXN3 gene resulting in a mutant protein (ATXN3). While in unaffected individuals this CAG repeat harbors 12 to 51 trinucleotides, in patients with Machado-Joseph disease contains 55 to 88 CAG repeats. As each CAG trinucleotide in the ATXN3 gene encodes one amino acid glutamine (Q), the disease protein harbors a stretch of continuous Qs, also known as polyglutamine (polyQ) tract.

Parkinson’s disease that is characterized by loss of dopaminergic neurons can be caused either by genetic mutations or by environmental factors. Mutations in the genes encoding the protein a-synuclein and the enzyme tyrosine hydroxylase (a crucial enzyme for the production of dopamine) are amongst the genetic causes of patients with Parkinson’s disease.

Continue reading “Byproducts of canola oil production show therapeutic potential for MJD and Parkinson’s Disease”

Saiba mais: O que são os modelos de Caenorhabditis elegans?

O que é C. elegans?

Se você leu o título deste artigo e não fazia ideia do que é Caenorhabditis elegans, você não está sozinho! Caenorhabditis elegans, mais comumente conhecido como C. elegans, são vermes microscópicos que normalmente crescem até 1 mm de comprimento. C. elegans são naturalmente encontrados em todo o mundo em solos onde há vegetação podre. Se você estiver se sentindo corajoso, tente localizá-los no adubo caseiro da sua casa! Embora esses vermes sejam menos familiares ao público em geral, C. elegans são bem conhecidos pelos cientistas, pois o estudo desses pequenos vermes nos ensinou muito sobre doenças humanas.

Por que C. elegans é usado como modelo?

elegans foi isolado pela primeira vez em 1900 e, desde o final da década de 1960, tem sido usado para “modelar” doenças humanas. Isso ocorre porque C. elegans e humanos compartilham algumas características fisiológicas comuns e têm uma sobreposição significativa em seus códigos genéticos. O SCAsource publicou anteriormente um Saiba Mais em modelos de camundongos, amplamente utilizados na pesquisa de ataxia. Embora C. elegans não seja amplamente utilizado na pesquisa de ataxia, há muitas vantagens em usar C. elegans como modelo:

  • C. elegans é de manutenção barata, permitindo a triagem de milhares de medicamentos a um custo relativamente baixo. Uma vez administrados, os cientistas podem estudar os efeitos das drogas no movimento, desenvolvimento e função do sistema nervoso de C. elegans.
  • C. elegans é fácil de cultivar em laboratório.
  • C. elegans são hermafroditas auto-fertilizantes, o que significa que eles podem se reproduzir sem um parceiro sexual. Um único hermafrodita pode produzir de 300 a 350 filhotes por um período de três dias, permitindo que os cientistas estudem facilmente um grande número de vermes que possuem as mesmas características genéticas.
  • Os cientistas podem manipular facilmente o genoma de C. elegans para estudar muitas doenças humanas.
  • Como C. elegans é transparente, seus órgãos internos, incluindo o sistema nervoso, podem ser visualizados sem dissecção.

Como C. elegans pode ser usado para estudar a neurodegeneração?

O sistema nervoso de um C. elegans é composto de algumas centenas de neurônios, o que é relativamente simples comparado ao cérebro humano (que contém cerca de 86 bilhões de neurônios). Devido a essa simplicidade, os cientistas usaram C. elegans para desenvolver modelos para várias doenças neurodegenerativas, incluindo Alzheimer, Parkinson, ataxia de Friedreich e, mais recentemente, ataxia espinocerebelar do tipo III (SCA3). O modelo SCA3 C. elegans foi desenvolvido por um grupo de pesquisa em Portugal liderado pela Dra. Patrícia Maciel, e é o primeiro do gênero no campo da ataxia espinocerebelar. Esses vermes expressam a proteína humana que causa SCA3 em todos os seus neurônios, resultando em disfunção motora de início adulto que se assemelha ao que vemos em pacientes com SCA3.

uma imagem microscópica de neurônios em dois c. vermes elegans. Um é um neurônio suave e saudável. Um deles tem um neurônio danificado que tem uma ruptura nele.
Uma imagem de microscopia dos neurônios de C. elegans colorida em verde. Imagem cortesia de Kim Pho.

A neurodegeneração (dano / morte de neurônios) em C. elegans é monitorada marcando os neurônios com um marcador que brilha em verde sob um tipo específico de luz. A saúde dos neurônios é então avaliada, possibilitando determinar se a neurodegeneração ocorreu. A imagem acima mostra um neurônio saudável de C. elegans à esquerda, que parece intacto, comparado a um neurônio danificado de C. elegans, à direita, com uma ruptura (seta branca). Ser capaz de distinguir entre neurônios saudáveis ​​e danificados em C. elegans é muito útil, pois os cientistas podem usar essa ferramenta para testar diferentes maneiras de reparar ou proteger os neurônios. Se os cientistas forem capazes de retardar ou impedir a neurodegeneração em C. elegans, existe o potencial de que essa descoberta possa eventualmente ajudar a tratar a neurodegeneração humana também.

Espero que este breve resumo tenha lhe mostrado que existe um enorme potencial científico nesses minúsculos vermes! Compreender a biologia de C. elegans fornece informações sobre a biologia humana, como como ocorre a neurodegeneração e o que podemos fazer para impedi-la.

Se você quiser saber mais sobre os sistemas modelo da C. elegans, dê uma olhada no WormBook, Wormbase e WormAtlas.

Obrigado a Kim Pho, do laboratório do Dr. Lesley MacNeil da Universidade McMaster, por fornecer as imagens fluorescentes dos neurônios da C. elegans.

Saiba mais escrito por Katie Graham, editado pelo Dr. Lesley MacNeil, e traduzido para Português por Guilherme Santos, publicado inicialmente em: 03 de abril de 2020.