Machado-Josephdisease (MJD) is a hereditary neurodegenerative disorder that destroys the brainareas involved in muscle control. Although the disease is clearly caused by a mutationin the ATXN3 gene - resulting in an abnormal ataxin-3 protein that forms toxic aggregatesin the brain - the mechanism how MJD develops is unclear. And despite decadesof research no cure or treatment has been found. But now a study in the journal Brain by researchers from Universityof Coimbra in Portugal used a new approach to this old problem, and discovereda way to revert the disease’s neural damage and its symptoms in several animal models of MJD. The treatment consists in restoring the levels of ataxin-2, a molecule involved in protein regulation that is abnormally low both in patients and MJD animals.  
Although much work needs to be done to see if this kind of therapy could be used to patients, the fact that it works in several animal models of MJD, reverts the disease even when it is already established and that MJD patients also lack ataxia-2 - makes the results particularly  promising.

MJD  (also known as Spinocerebellar ataxia type 3 or SCA3) is rare, but can still show a remarkably high incidence (up to1:150) in more isolated populations. It is also a particularly difficult hereditary disease to cope with because of its characteristics.  Not only every child of sufferer has a 50:50 chance of developing it, but, in affected families, each new generation develops MJD earlier than the previous one.  And while patients’ brain faculties are left intact,their body is unremittingly destroyed trapping the individual. Symptoms start with lack of coordination, speech and swallow difficulties, and progress to various degrees of paralysis that can leave patients wheelchair-bound, totally dependent or simply dead. And if the mutation first appearedin the small Azorean island of Flores, now is spread all over the world,including in parts of the Australian aborigine community where MJD is already considered a serious problem.

 Despite all this,and the fact that the mutation behind MJD is known, researchers have yet to find any treatment even if only to delay the course of the disease. 

In an attempt to readdress the problem, in their new work Clévio Nóbrega, Pereira de Almeida and colleagues from the Center forNeuroscience and Cell Biology and the University of Pharmacy in Coimbra University, decided, for once, to not focus onataxin-3, but instead on a protein called ataxin-2. It has been suggested that ataxin-2 is abnormal in MJD but it was only recently, when this molecule was discovered to regulate protein production, that researchers started thinking that it could be relevant in MJD.

To investigate this possibility Nóbrega and colleagues looked for ataxin-2 in MJD patients using patients’ muscle cells, but also,post-mortem, MJD diseased brains. They discovered that in fact ataxin-2 was largely absent in individuals with MJD and what remained was in the ataxin-3 toxic aggregates. Looking at rodent models of the disease it was possible to show that this reduction was driven by the increase in the toxic mutant ataxin-3 deposits as MJD progressed.  

But what turned out to be really exciting was when the researchers restored the ataxin-2 levels to normal in the diseased animals. Remarkably, this led to a drastic reduction both in the number of toxic aggregates and in the neural destruction in the mice, and soon after their symptoms of the disease also saw a significant improvement . Since MJD patients have a similar lack of ataxin-2, these results suggest that maybe patients could be treated in a similar same way.

But exactly how does ataxin-2 affect the production of mutated ataxin-3 and MJD development? The answer, as Almeida’s team discovered, is a molecule called PABP.

Proteins are the key molecules to all the body’s reactions, and our DNA contains the instructions for their production. But to produce a new protein, the DNAinformation needs to be translated first into a molecule of RNA that can be “read” by our protein-producing “factories”,the ribosomes. PABP job is to react with the RNA to help its translation, and this PABP-RNA reaction is crucial to start the assembly of a new protein.

But ataxin-2 can also bind PABP.

By blocking PABP (so it did not bind ataxin-2) or using a PABP molecule incapable of binding ataxin-2, the  researchers quickly proved that this molecule was in fact key to the protective effect of ataxin-2 in MJD. So what is happening?

In MJD animals (and maybe also in humans) the disease reduces ataxin-2 levels, which become so low that hardly binds any PAPB molecules, leaving them available to push the production of the mutant ataxin-3 protein, and as result the disease fully progresses. But when ataxin-2 levels return to normal  in diseased animals, PABP will now bind to it, halting ataxin-3 production. Since the cells’ “housekeeping” mechanisms are constantly clearing the toxic aggregates from the brain, once the production of the mutant protein is halted,the aggregates and the neural damage start to disappear, and with them also the disease symptoms.

 Although these new results look promising – after all we can an effect on live diseased animals,even on those already with full symptomology, and we know that MJD patients also lack ataxin-2 - the researchers alert that much needs to be done to confirm these results and their relevance for clinic. But it’s an important step to, at the very least, understand better the disease, and is worth to keep an eye for what will happen next.