Interaction of Ataxin-1 and DNA repair proteins contributes to SCA1 disease onset and progression

Written by Dr. By Marija Cvetanovic Edited by Dr. Larissa Nitschke

Suart et al. show that Ataxin-1 interacts with an important DNA repair protein Ataxia telangiectasia mutated (ATM), and that reduction of ATM improves motor phenotype in the fruit fly model of SCA1, indicating DNA repair as an important modifier of SCA1 disease progression.

Each day, due to a combination of wear and tear from the normal processes in the cells, and environmental factors, such as irradiation, DNA in each of our cells can accumulate from 10,000 to 1,000,000 damages. If damaged DNA is left unrepaired, this can lead to loss of cell function, cell death, or a mutation that may facilitate the formation of tumors. To avoid these negative outcomes, cells take care of damaged DNA employing DNA damage response/repair proteins. Ataxia-telangiectasia mutated (ATM) protein is a critical part of DNA repair as it can recognize sites of DNA damage. It also helps recruit other proteins that repair DNA damage.

Mutations in the ATM gene cause autosomal recessive ataxia called Ataxia telangiectasia (AT). AT is characterized by the onset of ataxia in early childhood, prominent blood vessels (telangiectasia), immune deficiency, an increased rate of cancer, and features of early ageing.

An artist's drawing of four strands of DNA
DNA repair may be an important modifier of SCA1 disease progression. Photo used under license by Anusorn Nakdee/

Expansion of CAG repeats in the Ataxin-1 gene causes dominantly inherited Spinocerebellar Ataxia Type 1 (SCA1). A feature of SCA1 is that a greater number of repeats correlates to an earlier age of onset of symptoms and worse disease progression. The connection of DNA repair pathways and SCA1 was brought into focus in 2016 by a study by Bettencourt and colleagues. As longer CAG repeat tracts association with earlier ages at onset do not account for all of the difference in the age of onset authors searched for additional genetic modifying factors in a cohort of approximately 1000 patients with SCAs. They showed that DNA repair pathways significantly associate with the age at onset in SCAs, suggesting that genes with roles in the DNA damage response could provide new therapeutic targets (and hence therapeutics) in SCAs.

In this study, Suart et al. identify ATM as one such gene. Using irradiation and oxidizing agent to damage DNA and using imaging to follow ataxin-1 movement, authors first show that ataxin-1 is recruited to the site of DNA damage in cultured cells. They also demonstrate that SCA1 mutation slows down but does not prevent ataxin-1 recruitment to the sites of DNA damage.

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Failure to repair DNA damage may be linked to SCA3

Written by Dr. Ambika Tewari Edited by Dr. Maria do Carmo Costa

Mutations in Ataxin-3 protein prevent the normal functioning of a DNA repair enzyme leading to an accumulation of errors

Cells are bombarded by thousands of DNA damaging events each day from internal and external sources. Internal sources include routine processes that occur within cells that generate reactive byproducts, while external sources include ultraviolet radiation. This DNA damage can be detrimental to cells. But the coordination of many DNA repair proteins helps to maintain the integrity of the genome. This prevent the accumulation of mutations that can lead to cancer.

DNA repair proteins play very important roles in the nervous system. During development, cells are actively growing and dividing and can incur many errors during these processes. Therefore, it is not surprising that numerous DNA repair proteins are expressed in the mammalian brain to prevent the accumulation of DNA damage. To much DNA damage can produce devastating consequences.

Damaged DNA molecule
Ataxin-3 plays a role in a DNA repair pathway which fixes double-strand DNA break. If these breaks are not fixed, there are devastating consequences. Photo used under license by Rost9/

In fact, DNA repair deficiencies usually result in profound nervous system dysfunction in humans. Examples include neurodegeneration, microcephaly and brain tumors. Altered DNA repair signaling has been implicated in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. This implicates DNA repair proteins in genome maintenance in the nervous system. There are many different types of DNA damage and DNA repair. Each repair process has its own proteins and sequence of events that lead to either repair or cell death.

Ataxin-3 is known for its role in Spinocerebellar ataxia type 3 (SCA3), an autosomal dominant disorder caused by a repeat expansion in the ATXN3 gene. Symptoms are progressive and include prominent ataxia, impaired balance, spasticity and eye abnormalities. These symptoms are primarily a result of cerebellum dysfunction, but brainstem and spinal cord regions also show abnormalities in SCA3 patients. Recent studies have shown that ataxin-3 is part of a complex of proteins that repair single-strand DNA breaks. A crucial member of this complex, polynucleotide kinase 3’-phosphatase (PNKP), is actively involved in not only repairing single-strand but also double-strand breaks. Since the activity of PNKP is dependent on ataxin-3, this group of researchers were eager to investigate whether ataxin-3 also functioned in the repair of double-strand DNA damage.

Continue reading “Failure to repair DNA damage may be linked to SCA3”

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.

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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.

Snapshot: What are Caenorhabditis elegans models?

What are C. elegans?

If you read the title of this article and had no idea what Caenorhabditis elegans are, you are not alone! Caenorhabditis elegans, more commonly known as C. elegans, are microscopic worms that typically grow up to 1 mm in length. C. elegans are naturally found worldwide in soil where there is rotting vegetation. If you are feeling brave, you can try to locate them in your household compost! Although these worms are less familiar to the general public, C. elegans are well known to scientists, since studying these tiny worms has taught us a lot about human disease.

Why are C. elegans used as a model system?

C. elegans were first isolated in 1900 and, since the late 1960s, have been used to “model” human disease. This is because C. elegans and humans share some common physiological features and have a significant overlap in their genetic codes. SCAsource previously published a Snapshot on mouse models, which are widely used in ataxia research,. Although C. elegans are not used as widely in ataxia research, there are many advantages to using C. elegans as a model system:

  • C. elegans are inexpensive to maintain, allowing for the screening of thousands of drugs at a relatively low cost. Once administered, scientists can study the drugs’ effects on C. elegans movement, development, and nervous system function.
  • C. elegans are easy to grow in the laboratory.
  • C. elegans are self-fertilizing hermaphrodites, meaning that they can reproduce without a sexual partner. A single hermaphrodite can produce 300-350 offspring over a 3-day period, allowing scientists to easily study a large number of worms that have the same genetic characteristics.
  • Scientists can easily manipulate the genome of C. elegans to study many human diseases.
  • Because C. elegans are transparent, their internal organs, including the nervous system, can be imaged without dissection.

How can C. elegans be used to study neurodegeneration?

The nervous system of a C. elegans is made up of a few hundred neurons, which is relatively simple compared to the human brain (which contains about 86 billion neurons). Because of this simplicity, scientists have used C. elegans to develop models for several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Friedreich’s ataxia and, more recently, spinocerebellar ataxia type III (SCA3). The SCA3 C. elegans model was developed by a research group in Portugal led by Dr. Patrícia Maciel, and it is the first of its kind in the spinocerebellar ataxia field. These worms express the human SCA3-causing protein in all their neurons, resulting in adult-onset motor dysfunction that resembles what we see in SCA3 patients.

a microscope image of neurons in two c. elegans worms. One is a smooth, healthy neuron. One has a damaged neuron that has a break in it.
A microscopy image of C. elegans neurons coloured green. Image courtesy of Kim Pho.

Neurodegeneration (damage/death of neurons) in C. elegans is monitored by tagging neurons with a marker that shines green under a specific type of light. The health of neurons is then assessed, making it possible to determine if neurodegeneration has occurred. The image above shows a healthy C. elegans neuron on the left, which appears intact, compared to a damaged C. elegans neuron on the right, which has a break (white arrowhead). Being able to distinguish between healthy and damaged neurons in C. elegans is very useful, as scientists can use this tool to test different ways of repairing or protecting neurons. If scientists are able to slow or prevent neurodegeneration in C. elegans, there is potential that such a discovery could eventually help treat human neurodegeneration, as well.

I hope this short summary has shown you that there is a massive amount of scientific potential in these tiny worms! Understanding the biology of C. elegans provides insight into human biology, like how neurodegeneration occurs and what we can do to stop it.

If you would like to learn more about C. elegans model systems, take a look at WormBook, Wormbase, and WormAtlas.

Thank you to Kim Pho from Dr. Lesley MacNeil’s lab at McMaster University for providing the fluorescent images of C. elegans neurons.

Snapshot written by Katie Graham and edited by Dr. Lesley MacNeil.