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    A Treatment For Neurodegenerative Machado-Joseph Disease?
    By Catarina Amorim | July 23rd 2012 06:56 AM | 12 comments | Print | E-mail | Track Comments
    About Catarina

    After many years as a scientist (immunology) at Oxford University I moved into scientific journalism and public understanding of science. I am...

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    Researchers have moved a step closer to find a treatment for the fatal neurodegenerative disorder Machado-Joseph disease (MJD) after a Portuguese team from the Centre for Neurosciences at the University of Coimbra was able to halt the brain degeneration in mice, by blocking a molecule called calpain. Calpain are known to cut ataxin-3 (the mutant protein behind MJD) into fragments, and the study proves that these fragments are crucial to trigger the neurodegeneration. 

    If the work can be repeated in patients – and preliminary results suggest that it can – drugs to block calpain could become the first treatment ever capable of stopping MJD. Luis Pereira de Almeida, the research team leade, adds, “and even if we can not totally prevent the cleavage of ataxin-3, since this is a late-onset disease,to reduce its speed could just be enough to stop it to appear during the lifetime of the patients, what would be an incredible victory in a terrible disease.”

    MJD (also called spinocerebellarataxia type 3 , ataxia 3 or SCA3) is nothing short of terrible, a neurodegenerative disorder that causes ataxia (an incapacity to control the body’s movements) confining patients to a wheelchair and total dependence, the disease is fatal and have no treatments. And even if rare, in places where its incidence is at its highest - like the Portuguese Azorean island of Flores – it can affect as many as 1 in every 140 individuals. This, together with the fact that disease severity tends to increase as it passes from one generation to the next, and that it is transferred to half of all the children from affected parents, makes finding a treatment urgent.  

    Ataxia movements

    Ataxia abnormal movement (2 last rows). By Eadweard Muybridge (19 century) Photo from Boston Public Library

    We know that MJD is caused by an aberrant piece of DNA that multiplies inside the MJD1 gene (the longer the piece, the worst the disease) producing a mutant ataxin-3 protein that aggregates forming deposit sin the brain areas affected by the disease. What we do not know is what leads to neurodegeneration, making it harder to develop treatments capable of stopping the process.

    In the study now published, Ana Simões (the work’s first author), Pereira de Almeida and colleagues look into a new therapies through another mystery of MJD – the reason why normal ataxin-3 “lives” outside of the cells’ nucleus, while the deposits of its mutant form are found inside (despite the mutant protein be bigger so, supposedly, have more difficulty to cross into the nucleus). The reasoning being, that if they could understand how this happens,they could stop it,  interfering with the disease.

    And this is where ataxin-3 fragments step in - the “toxic fragment hypothesis” is a theory that claims that some neurodegenerative disorders are triggered by the production of toxic fragments from the mutant protein behind the disease. Alzheimer’s disease, has been linked to it for example, and more recently also MJD. In fact, it has been shown recently that the mutantataxin-3, broken down by calpain, produces toxic fragments that are able not only of escaping the cell’s quality control mechanisms but also of triggering ataxin-3aggregation (that will lead to the brain deposits). And if MJD is triggered by toxic fragments produced by calpain this would explain how the abnormal deposits get into the nucleus (since are the fragments and not the protein that enter) and also, finally, give us a way to stop MJD (by blocking calpain). 

    So could calpain be the key to MJD neurodegeneration, and its treatment? Pereira de Almeida’s group in the work now published investigate the possibility with the help of calpain only known inhibitor in the body, a molecule called calpastatin (or CAST). The idea being that if calpain is important for MJD, CAST will be able to stop it.

    Using mice with different levels of CAST in the brain as well as the mutant ataxin-3, the researchers discovered that putting high quantities of CAST in MJD mouse brains reduced the abnormal protein deposits, as well as the neurodegeneration and the neural dysfunction typical of the disease. These CAST treated animals also had lower calpain activity (when compared with “normal” MJD mice), proving that CAST was affecting calpain. The hypothesis that CAST was acting by stopping the toxic fragments formation was further confirmed when fragments of the mutant protein were found in high quantities in diseased animals, but in much reduced numbers in those treated with high CAST levels.

    Simões and colleagues also found that CAST seemed to have a role in the actual disease – there was much less CAST in the brain of diseased mice than in healthy ones, and when the mutant ataxin-3 levels increased in MJD mice brains, CAST disappeared (apparently deleted by the mutant protein?).

    These results show, for the first time in live subjects (mice), a connection between the breakdown of the mutantataxin-3, the formation of abnormal protein deposits and the neural damage that provokes MJD. They also prove that the toxic fragments are crucial to trigger the brain destruction. Like Pereira explains, “it is like ataxin-3 becomes “spiked” by calpains, with these “armed”fragments forcing the access to the cells’ control centres where they block themost diverse functions and cause cell death. Because they are small they have better capability to enter the cell nucleus to provoke damage.” The results also open the door to similar investigations in other neurodegenerative disorders with a potential “toxic fragments’ link. 

    But most important of all is the fact that the work shows that CAST can stop MJD neurodegeneration. The question now is, can it be repeated in humans? Some preliminary but very promising experiments by Pereira deAlmeida’s team show that CAST levels are also lower than normal in the brain of MJD patients, suggesting a similar disease mechanism in us and mice (and so also a similar therapeutic effect for CAST) which is great news for future efforts. The group is already testing oral medication capable of blocking calpain, in animals.

    Brain 2012 doi:10.1093/brain/AWS177  “Calpastatin-mediated inhibition of calpains in themouse brain prevents mutant ataxin-3 proteolysis, translocation to the nucleusand aggregation, relieving Machado-Joseph disease”

    Comments

    Are there any trials going on for MJD for humans?
    Are there any medications that help with symptoms for MJD?

    Hi, how secure is treatment to be developed in humans?
    Are you looking for volunteers?
    Pelase contact me, Im from México, my last name is Olascoaga, it might sound familiar to you in this disease

    amorca
    Dear Liz I just wrote about the discovery, I am not the scientist involved. Like I said to Saind, your doctor and support groups are the best places to find what is the latest in the field including human trials
    Best of luck

    Catarina
    amorca
    Sandi that I know there aren't yet any treatments , except to ammeliorate the symptoms. But the person to ask is your doctor, he/she will be the person best informed about any of those questions. Another alternative are MJD support groups, they tend to be very well informed
    Good luck 
    Any idea how long it will take for a drug to be available to humans to block the calpain indicated in the article?

    amorca
    A few years still Sandi. And we still need to be sure that it works in the same way in humans. The good news is that they are trying to develop calpain inhibitors  for Alzheimer's patients so  that could help to speed up the process. 
    Dear Catrina,

    Please tell me if it is helpful for other types of Ataxia also and please helpout if you have any Mail Address of the Drs
    who have searched this medicine for Ataxics.

    Would like to contact then ASAP.

    Regards
    Sakshi Nanda

    Dear Catrina,

    Please tell me if it is helpful for other types of Ataxia also and please helpout if you have any Mail Address of the Drs
    who have searched this medicine for Ataxics.

    Would like to contact then ASAP.

    Regards
    Sakshi Nanda

    Dear Catrina,

    Please tell me if it is helpful for other types of Ataxia also and please helpout if you have any Mail Address of the Drs
    who have searched this medicine for Ataxics.

    Would like to contact then ASAP.

    Regards
    Sakshi Nanda

    amorca
    Dear Sakshi , in other ataxias other genes are affected so the mechanisms is also different. And these are not doctors but researchers , they will not be able to help with the disease. Also these results are  just the beginning  of a long path until a medicine is available - and the results still need further confirmation in humans. 
    To find researchers doing medical trials, or the latest treatments ask your own doctor or look into support groups , the american ones specially tend to be very well informed
    Best of luck

    Hi I live in Australia and have Mjd I. Am 32yrs old my dad died of Mjd when he was 50 and as his carer know what he went through I am gettin worse as time goes by and a m really strugglin to walk and swallow food and communicate is there any help in Australia .please help I am really startin to worry bout my future

    Regards Darren

    amorca
    As usual the best place to find those things Darren is your doctor and/or the net. A quick web search gave me this website  http://www.mjd.org.au   It´s for indigenous people but I am sure they will be able to help or at least direct you. They also have links to other organizations  in  http://www.mjd.org.au/19-resources.html 

    including the australian spinocerebral ataxia foundation ( Spinocerebella Ataxia Australia )
    Best of luck