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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Identifying FDA-approved molecules to treat SCA6

Written by Dr Hannah Shorrock Edited by Dr. Larissa Nitschke

Pastor and colleagues identify FDA-approved small molecules that selectively reduce the toxic polyglutamine-expanded protein in SCA6.

Selectively targeting disease-causing genes without disrupting cellular functions is essential for successful therapy development. In spinocerebellar ataxia type 6 (SCA6), achieving this selectivity is particularly complicated as the disease-causing gene produces two proteins that contain an expanded polyglutamine tract. In this study, Pastor and colleagues identified several Food and Drug Administration (FDA) approved small molecules that selectively reduce the levels of one of these polyglutamine-containing proteins without affecting the levels of the other protein, which is essential for normal brain function. By using drugs already approved by the United States Food and Drug Administration to treat other diseases, referred to as FDA-approved drugs, the team hopes to reduce the time frame for pre-clinical therapy development.

SCA6 is an autosomal dominant ataxia that causes progressive impairment of movement and coordination. This is due to the dysfunction and death of brain cells, including Purkinje neurons in the cerebellum. SCA6 is caused by a CAG repeat expansion in the CACNA1A gene. CACNA1A encodes two proteins: the a1A subunit, the main pore-forming subunit of the P/Q type voltage-gated calcium ion channel, as well as a transcription factor named a1ACT.

The a1A subunit is essential for life. Its function is less affected by the presence of the expanded polyglutamine tract than that of a1ACT. The transcription factor, a1ACT, controls the expression of various genes involved in the development of Purkinje cells. Expressing a1ACT protein containing an expanded polyglutamine tract in mice causes cerebellar atrophy and ataxia. While reducing levels of the a1A subunit may have little effect on SCA6 disease but impact normal brain cell function, reducing levels of a1ACT may improve disease in SCA6. Therefore, Pastor and colleagues decided to test the hypothesis that selectively reducing levels of the a1ACT protein without affecting levels of the a1A protein may be a viable therapeutic approach for SCA6.

Colorful pile of medicines in blister packs which color are White, Yellow, Black and Pink pills.
By using drugs already approved by the FDA, the team hopes to reduce the time frame for pre-clinical therapy development. Photo used under license by Wanchana Phuangwan/
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Eliminación de la proteína ataxina-2 agregada como vía terapéutica para SCA2

Escrito por el Dr. Vitaliy Bondar Editado por el Dr. Hayley McLoughlin. Publicado inicialmente en el 5 de febrero de 2021. Traducción al español fueron hechas por FEDAES y Carlos Barba.

Una nueva investigación sugiere que la proteína ataxina-2 mutante abruma a las células en SCA2, lo que lleva a una disminución de la autofagia y la eliminación de las proteínas dañadas.

Se pueden hacer muchas comparaciones entre células y seres humanos. Al igual que los humanos, las células pueden acumular basura y desechos en ciertos momentos y este desorden con el tiempo se vuelve problemático e incluso tóxico. Esto es precisamente lo que Jonathan Henry Wardman y sus colegas de la Universidad de Copenhague decidieron investigar a nivel celular. Preguntaron si la falta de una eliminación adecuada de las proteínas defectuosas de la enfermedad afecta la supervivencia y el bienestar celular.

Los investigadores optaron por estudiar células derivadas de un paciente que tiene ataxia espinocerebelosa tipo 2 (SCA2). La causa de SCA2 es la expansión de la repetición CAG en el gen ATAXIN-2 , que codifica la cadena de aminoácidos de poliglutamina en una proteína de unión al ARN , ataxina-2. Se encuentra que la proteína ATXN2 expandida poliQ defectuosa se agrega dentro de la célula y las horas extraordinarias pueden afectar su supervivencia. La acumulación de productos proteicos agregados derivados de genes mutados es un sello distintivo de muchos tipos de ataxias espinocerebelosas, así como de otras formas de trastornos neurodegenerativos como la enfermedad de Parkinson.

No está claro cómo la agregación de proteínas afecta la supervivencia celular. Sin embargo, se han correlacionado múltiples defectos celulares con la agregación de ataxina-2. Por ejemplo, se ha informado que las mitocondrias que generan energía para una célula funcionan de manera anormal en modelos celulares SCA2. Además, un mecanismo de depuración celular, llamado autofagia , que es responsable de limpiar los compartimentos celulares defectuosos y ciertas proteínas rotas, se muestra menos eficaz en varios modelos de SCA2. Estos mecanismos los autores decidieron investigar en su artículo de investigación recientemente publicado.

scientist using microscope
Una nueva investigación que utiliza células SCA2 arroja luz sobre las causas de los síntomas de la enfermedad. Foto de Chokniti Khongchum en

Los científicos identificaron por primera vez la evidencia de disfunción celular SCA2 mediante la detección de una elevación significativa de los niveles de caspasa-9 y caspasa-8. Son proteínas que indican estrés celular y muerte. Los autores plantearon la hipótesis de que dicha disfunción celular puede deberse a la acumulación de ataxina-2 defectuosa. Para probar esta hipótesis, decidieron bloquear sistemáticamente dos vías celulares que procesan proteínas defectuosas: proteostasis y autofagia.

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Clearing aggregated ataxin-2 protein as a therapeutic avenue for SCA2

Written by Dr. Vitaliy Bondar Edited by Dr. Hayley McLoughlin

New research suggests that mutant ataxin-2 protein overwhelms cells in SCA2, leading to decreased autophagy and clearance of damaged proteins.

Many comparisons can be made between cells and human beings. Just like humans, cells can accumulate junk and waste at certain times and this clutter overtime becomes problematic and even toxic. This is precisely what Jonathan Henry Wardman and colleagues from the University of Copenhagen decided to investigate on a cellular level. They asked whether the lack of appropriate clearance of faulty disease proteins effect cellular survival and wellbeing.

The researchers chose to study cells derived from a patient that has Spinocerebellar ataxia type 2 (SCA2). The cause of SCA2 is CAG repeat expansion in the ATAXIN-2 gene, which encodes polyglutamine amino acid chain in an RNA-binding protein, ataxin-2. The faulty polyQ expanded ATXN2 protein is found to aggregate inside the cell and overtime can affect its survival. Accumulation of aggregated protein products derived from mutated genes is a hallmark of many types of spinocerebellar ataxias as well as other forms of neurodegenerative disorders such as Parkinson’s disease.

It is unclear how protein aggregation impacts cellular survival. However, multiple cellular defects have been correlated with ataxin-2 aggregation. For instance, mitochondria which generates energy for a cell, has been reported to abnormally function in SCA2 cellular models. Additionally, a cellular clearance mechanism, called autophagy, which is responsible for clearing faulty cellular compartments and certain broken proteins is shown to be less effective in various SCA2 models. These mechanisms the authors decided to investigate in their recently published research article.

scientist using microscope
New research using SCA2 cells sheds light on what causes disease symptoms to occur. Photo by Chokniti Khongchum on

The scientists first identified evidence of SCA2 cellular dysfunction through detection of significant elevation of caspase-9 and caspase-8 levels. These are protein which indicate cellular stress and death. The authors hypothesized that such cellular dysfunction may arise from accumulation of faulty ataxin-2. In order to test this hypothesis, they decided to systematically block two cellular pathways that process defective proteins: proteostasis and autophagy.

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