Subproduto da produção do óleo de canola apresenta potencial terapêutico para as doenças de Machado-Joseph e Parkinson

Escrito por Dr. Maria do Carmo Costa, editado por Dr. Hayley McLoughlin. Inicialmente publicado em 24 de abril de 2020. Traduzido para o português por Priscila P. Sena.

Em um trabalho de colaboração utilizando modelo animal, pesquisadores de Portugal e do Reino Unido descobrem um subproduto do óleo de canola promissor para o tratamento das doenças de Machado-Joseph (ou ataxia espinocerebelar do tipo 3 – SCA3) e Parkinson.

Compostos isolados ou extratos (contendo uma mistura de compostos) de determinadas plantas têm se mostrado promissores como potenciais drogas anti-envelhecimento, ou como drogas terapêuticas para doenças neurodegenerativas. Alguns desses compostos ou extratos vegetais podem aumentar a capacidade celular de combater o estresse oxidativo anormal, típico do envelhecimento e de doenças neurodegenerativas. A doença de Machado-Joseph (também conhecida como ataxia espinocerebelar do tipo 3) e a doença de Parkinson são duas doenças neurodegenerativas nas quais a incapacidade celular de combater o estresse oxidativo contribui para a perda neuronal. Nesse estudo, os grupos do Dr. Thoo Lin e Dr. Maciel fizeram uma parceria para testar o potencial terapêutico do bagaço de colza (“rapeseed pomace”, RSP), um extrato residual com propriedades antioxidantes obtido após a produção do óleo de canola. Os experimentos foram realizados em modelo nematódeo (Caenorhabditis elegans) das doenças de Machado-Joseph e Parkinson.

Canola field with snowcapped mountains in the background, July 1990
Plantação de canola com montanhas cobertas de neve ao fundo, cortesia de imagem da USDA NRCS Montana on Flickr.

A doença de Machado-Joseph é uma ataxia neurodegenerativa dominante, causada por uma expansão trinucleotídica CAG no gene ATXN3 que resulta em uma proteína mutante (ATXN3). Enquanto em indivíduos não afetados essa expansão trinucleotídica contém de 12 a 51 repetições CAG, em pacientes de Machado-Joseph essa expansão varia entre 55 e 88 repetições. Como cada CAG no gene ATXN3 codifica um aminoácido glutamina (Q), a proteína mutante contém um trecho de Qs contínuos, conhecido como poliglutamina (polyQ).

A doença de Parkinson, caracterizada pela perda de neurônios dopaminérgicos, pode ser causada tanto por mutações genéticas quanto por fatores ambientais. Mutações nos genes codificadores da proteína α-sinucleína e da enzima tirosina hidroxilase (uma enzima crucial para a produção de dopamina) estão entre as causas genéticas da doença de Parkinson.

Nesse estudo, Pohl, Teixeira-Castro e colaboradores utilizaram modelos nematódeos para a doença de Machado-Joseph, geneticamente modificados para a produção neuronal da proteína mutante humana ATXN3. A proteína mutante forma agregados proteicos nos neurônios dos nematódeos e causa problemas de motilidade, replicando aspectos da doença de Machado-Joseph em humanos.

Os pesquisadores também utilizaram nematódeos modificados geneticamente para expressar a proteína ATXN3 normalmente expressa em humanos não afetados pela doença de Machado-Joseph. Esses nematódeos apresentam movimentos normais e a proteína ATXN3 não forma agregados proteicos nos neurônios, o que reproduz a condição normal humana.

Modelos nematódeos que apresentam perda de neurônios dopaminérgicos também foram utilizados, representando a doença de Parkinson causada tanto por fatores genéticos quanto por fatores ambientais. Eles utilizaram nematódeos geneticamente modificados para a produção da proteína α-sinucleína humana, ou para a superexpressão da enzima tirosina hidroxilase, ou ainda nematódeos tratados com um composto químico que leva à morte de neurônios dopaminérgicos.

Os autores mostraram nesse estudo que a administração de RSP, um subproduto da produção do óleo de canola, aos modelos nematódeos das doenças de Machado-Joseph e Parkinson, reduz determinados sinais dessas doenças. Resumidamente, os modelos nematódeos da doença de Machado-Joseph tratados com RSP apresentaram uma recuperação dos movimentos a um nível comparável aos animais não afetados, e os modelos nematódeos da doença de Parkinson tratados com RSP mostraram uma preservação dos neurônios dopaminérgicos.

Em seguida, os pesquisadores mostraram que o tratamento com RSP recuperou os nematódeos de certos sinais das doenças de Machado-Joseph e Parkinson através da ativação de vias celulares que protegem contra o estresse oxidativo. Especificamente, os autores encontraram evidências de uma via protetora em particular, conhecida como resposta celular antioxidante dependente de glutationa S-transferase 4 (GST-4), que foi ativada em modelos nematódeos das doenças de Machado-Joseph e Parkinson tratados com RSP.

Ainda que sejam necessários mais estudos, particularmente em animais vertebrados, para que se compreenda completamente como o extrato de RSP recupera o organismo de sinais das doenças de Machado-Joseph e Parkinson, a enzima GST-4 parece ser um bom alvo terapêutico para essas doenças. Esse estudo, acima de tudo, demonstra que o aumento de defesas particulares do organismo contra o estresse oxidativo é uma rota potencial para o desenvolvimento de estratégias terapêuticas para as doenças de Machado-Joseph e Parkinson.

Palavras-chave

Repetições CAG: um trecho de DNA composto pela sequência CAG repetida muitas vezes. Todos nós temos repetições CAG em alguns genes, mas se essas repetições excederem um limite de tamanho elas podem causar doenças, como é o caso da doença de Machado-Joseph.

Caenorhabditis elegans: um animal bem pequeno, parecido com uma minhoca, denominado nematódeo. C. elegans são organismos muito simples, mas podem ser utilizados para aprendermos mais sobre organismos mais complexos, como o organismo humano. Para aprender mais, visite o nosso Snapshot em C. elegans.

Neurônios dopaminérgicos: um tipo de neurônio que produz dopamina, encontrado no sistema nervoso. Apesar de representarem menos de 5% de todos os neurônios do corpo, eles exercem um papel importante no movimento, humor e estresse.

Estresse oxidativo: um tipo de perturbação do funcionamento normal de uma célula, causado por um desbalanço dos níveis de espécies reativas de oxigênio. Essas espécies de oxigênio são produzidas como um subproduto normal do metabolismo celular e geralmente são eliminadas pela célula sem grandes transtornos. Quando as células são incapazes de eliminar de forma suficiente essas espécies reativas de oxigênio, essas moléculas começam a acumular e causar danos a componentes que formam estruturas críticas da célula, como lipídeos, proteínas e o DNA. Conforme envelhecemos, as células naturalmente se tornam menos eficientes em eliminar espécies reativas de oxigênio, e experimentamos um nível mais alto de estresse oxidativo.

Declaração de conflito de interesse

Os autores e o editor declaram não haver conflito de interesse.

Dois dos autores do artigo original (P. Maciel e F. Pohl) contribuem para o SCAsource. Nenhum desses autores teve qualquer contribuição à escrita ou edição desse resumo.

Citação do artigo revisado

Pohl F, Teixeira-Castro A, Costa M, Lindsay V, Fiúza-Fernandes J, Goua M, Bermano G, Russell W, Maciel P, Kong Thoo Lin P. GST-4-dependent suppression of neurodegeneration in C. elegans models of Parkinson’s and Machado-Joseph disease by rapeseed pomace extract supplementation. Frontiers in neuroscience. 2019;13:1091. doi: 10.3389/fnins.2019.01091

Mutated ataxin-1 protein forms harmful, doughnut-shaped aggregates that are not easily destroyed

Written by Brenda Toscano Marquez   Edited by Marija Cvetanovic

Insoluble clumps of mutated ataxin-1 capture essential proteins and trigger the creation of toxic reactive oxygen species.

All proteins produced by our cells consist of long chains of amino acids that are coiled and bent into a particular 3D structure. Changes in that structure can cause serious issues in a cell’s function, sometimes resulting in disease. Spinocerebellar ataxia type 1 (SCA1) is thought to be the result of one such structural change. The cause of SCA1 is a mutation that makes a repeating section of the ATXIN1 gene abnormally long. This repeated genetic code, “CAG,” is what encodes the amino acid glutamine in the resulting ataxin-1 protein. Therefore, in the cells of patients with SCA1, the Ataxin-1 protein is produced with an expanded string of glutamines, one after the other. This polyglutamine expansion makes the mutated ataxin-1 protein form clumps in many different types of cells – most notably, though, in the cells most affected in SCA1: the brain’s Purkinje cells.

Recent research suggests that these clumps, or “aggregates,” not only take up space in the cell, but that the act of ataxin-1 proteins clustering together might even be beneficial in early stages of disease (it’s possible that the proteins wreak less havoc when they’re in large clumps, rather than all floating around individually). However, another line of research suggests that ataxin-1 aggregates might also be toxic, triggering signals that lead to the cell’s death. As such, how exactly these aggregates affect the deterioration of cells has remained an important question in SCA1 research.

n a search for answers, an international team led by Stamatia Laidou designed a unique cell model of SCA1 to track the development of ataxin-1 aggregates. Their study, published in a recent paper, made use of normal human mesenchymal stem cells that had been engineered to make a modified version of the ataxin-1 protein. In these cells, ataxin-1 was produced not only with the SCA1-causing expansion, but also with a marker protein attached to its end. This marker, known as “green fluorescent protein” (GFP), is used extensively in biological research because it glows under fluorescent light.

doughnut with white and pink sprinkles
Laidou and colleagues have observed mutated ataxin-1 clumps that cause cell stress. Photo by Tim Gouw on Pexels.com

Using this to their advantage, Laidou and her team used a fluorescent microscope to follow the formation of ataxin-1 aggregates over the course of 10 days. The abnormal protein first started accumulating in the nucleus as small dots. As time went on, these dots started blending together, increasing in size. By ten days, the ataxin-1 aggregates had grown even more, forming a doughnut-shaped structure that occupied most of the cell’s nucleus – a crucial structure that houses the cell’s genetic information. These results were intriguing, since the accumulation of normal, non-expanded Ataxin-1 protein does not result in an aggregate with a doughnut shape.

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Snapshot: What is Omaveloxolone?

A new therapeutic compound shows promise to treat Friedrich’s ataxia.

What is Friedrich’s ataxia (FA)?

Friedrich’s ataxia is a genetic neurodegenerative disease that affects many organs, most notably nerves, muscles, and heart. FA is a recessive ataxia. Symptoms typically present in childhood and result in significant physical disability. Cognition (thinking, memory) remains intact.

Some of the symptoms a person with FA may experience include ataxia (loss of movement coordination), fatigue, muscle weakness, cardiomyopathy (heart issues), scoliosis (curvature of the spine) and sensory impairments (vision, hearing). Life expectancy is reduced as a result of the disease.

The genetic change that is present in FA affects the production of a protein called frataxin. Frataxin deficiency leads to abnormal iron accumulation in mitochondria.  As mitochondria are critical for energy metabolism and other important functions in cells, their dysfunction causes faulty energy production and undesirable toxicity in the form of reactive oxygen species.

There is currently no treatment available to patients with FA.

white medical pills in the shape of a question mark
What is Omaveloxolone? How could it help people with Friedrich’s Ataxia? Photo by Anna Shvets on Pexels.com

How does Omaveloxolone work?

Omevaloxolone is a synthetic compound. It works by counteracting deficits seen in disease at the cellular level. Omevaloxolone promotes Nrf2, which works to activate a series of defence mechanisms that help cells handle oxidative stress (mentioned above). Nrf2 is also important for improving the energy production machinery mitochondria require to function efficiently. Thus, by activating Nrf2, Omevaloxolone is thought to mitigate oxidative damage, improve energy production, and promote neuroprotection. Additionally, Omevaloxolone and similar compounds exhibit anti-inflammatory action.

What exactly has been validated?

In the MOXIe clinical trial, study participants with FA from several countries were randomized to either daily omaveloxolone (drug) or placebo (control). Their neurological function, activities of daily living, and ataxia were assessed at baseline (at the beginning) and after 48 months of receiving treatment. At the end of this period, the data showed statistically significant improvement in each of these measures. Participants who received omaveloxolone fared better than those who did not (placebo). Additionally, participants who received omaveloxolone saw improvements after treatment compared to their own baseline at the beginning of the study.

What is happening next?

The next step in testing omaveloxolone is to have a long-term study to examine its safety (and any side effects) over the course of a few years. Instead of having a control group in this type of study, called an open-label extension, now everyone enrolled received the same amount of omaveloxolone. This study is already underway and is expected to be completed by 2022. There have been some modifications to the long-term safety study in response to COVID-19, but Reata doesn’t expect there to be a significant delay in their timelines.

If you would like to learn more about omaveloxolone, take a look at these resources by the Reata Pharmaceuticals and ClinicalTrials.gov. To learn more about Friedrich’s Ataxia, visit the Friedrich’s Ataxia Research Alliance website.

Snapshot written by Dr. Judit M. Pérez Ortiz and edited by Larissa Nitschke.

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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Mitochondrially Stressed

Written by Dr. Judit M. Pérez Ortiz Edited by Dr. Brenda Toscano Márquez

Scientists describe how SCA2 oxidative stress can affect mitochondrial function, and potentially how to fix it

Mitochondrial Stress

We all have experienced stress. When cramming for an exam last minute, or getting ready for a job interview, our bodies feel stress-related energetic drive and hyperfocus. Small bursts of stress can help us get through specific demands, but too much constant stress takes a toll and makes it difficult for us to function. It turns out that the cells in our bodies experience stress too! While the stress response that we experience in our hectic lives is associated with stress hormones, the stress cells experience is from another source altogether – mitochondria. Scientists at the University of Copenhagen in Denmark identified a novel link between mitochondrial oxidative stress and spinocerebellar ataxia type 2 (SCA2).

Classically, we learn that mitochondria are the powerhouse of the cell responsible for making the bulk of the energy currency that cells need to work and survive, ATP. To do this, mitochondria rely on a cooperative group of protein complexes called the Electron Transport Chain (ETC). Albeit via a more sophisticated procedure than a hot-potato game, the complexes mediate chemical reactions (called redox reactions) by which “hot” electrons are passed from high energy molecules to lower-energy molecules, and so on. The final electron recipient (“acceptor”) is a stable oxygen molecule and their encounter is used to make water. The activity of the ETC helps harness energy that is ultimately used to make ATP in what is called oxidative phosphorylation.

Sometimes not all the electrons make it through; the hot potato “drops”. Electrons leak out and react directly with molecular oxygen (chemical formula O2), turning unstable superoxide (chemical formula O2) which in turn, can create other reactive oxygen species (ROS). The extra electron in superoxide gives it a negative charge and makes it highly reactive and toxic. Just like the small amount of stress primes your body for a challenge to come, low levels of ROS hints the cell that it needs to make some changes to optimize the system. As the superoxide levels go up, cells make more antioxidant enzymes available to keep ROS in check. Antioxidant enzymes convert the highly reactive superoxide to a less reactive hydrogen peroxide (like the one in your bathroom cabinet). This, in turn, can be converted to water and ordinary oxygen molecules. In a word, the antioxidants “detox” the cells from ROS insult.

The cell becomes “stressed out” when there’s too much ROS that can’t be compensated for. This stress caused by oxygen or “oxidative stress” can damage DNA, fats, and proteins that affect the cell and organism as a whole. For example, oxidative stress can contribute to heart disease, diabetes, cancer, and neurodegenerative diseases.

cartoon drawing of human cells that are blue
An artist’s drawing of human cells under a microscope.

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