New Hope for Treatment of Machado-Joseph Disease

New Hope for Treatment of Machado-Joseph Disease

A team of scientists from the University of Coimbra, in Portugal, was able to identify and block one of the basic mechanisms responsible for the degeneration of brain tissue that characterizes the terrible and incurable degenerative Machado-Joseph disease (MJD). The results obtained in mice are yet to be confirmed in humans, but open the door and give hope for what could be the very first effective treatment of this genetic disease.

Although it is relatively rare in most of the world, Machado-Joseph disease affects one in 4,000 people of Portuguese ancestry in New England (USA) and one in 140 on the island of Flores, in the Azores. Machado-Joseph disease, also called spinocerebellar ataxia type 3 (SCA3), affects the cerebellum, which is responsible for movement coordination, muscle tone and control of balance. It was first described in 1972 as an autosomal, dominantly inherited neurodegenerative disease.

Unlike many medical conditions, the disease was not named after researchers but rather after the first two families from which first reports were made, the Machado and Joseph families, from Azores. William Machado was born on the island of São Miguel, Azores, and he emigrated to Massachusetts in late nineteenth century, where he and his family established residence. António Jacinto Bastiana was born on the island of Flores in 1815 and emigrated to San Francisco, California, in 1845. He later adopted the name of Antone Joseph and died in 1870, but not before raising seven children. Today, California is home to about 600 descendants of Antone Joseph. Machado-Joseph disease is dominantly-inherited and if one parent is affected the children have a 50% probability of developing the disease. It can appear as early as during childhood or as late as at 70 years old with symptoms of varying severity.

Typically, Machado-Joseph disease will cause loss of control of balance and stiffness, which causes patients to appear drunk or suffering from Parkinson's disease. Other symptoms include muscle spasms, trouble with speech and swallowing, visual disturbances and uncontrolled eye movement, sleep disorders and cognitive problems that progress and worsen with time leading to eventual paralysis. Usually, patients die of lung infections often caused by food intake. This disease is also particularly tragic as its gravity increases over generations. In 1994, the cause of Machado-Joseph disease was shown to be due to a pathogenic mutation within a single gene, MJD1 (now renamed ATXN3), localized in chromosome 14 and identified as a CAG repeat expansion.3 This leads to the synthesis of an abnormal protein, ataxin-3, that forms lethal deposits within neurons.

The team in Coimbra managed to unravel the fragmentation process, confirming that this process and cerebellar degeneration are indeed related. More precisely, they showed that the mutant ataxin-3 is cut to pieces by a molecule called calpain. When calpain is inactivated by high levels of calpastatin, a natural inhibitor of calpain present in the body, the ataxin-3 neurotoxic fragments and their deposits in neurons are drastically reduced and destruction of brain cells is interrupted.

This discovery shows promise for the potential to stop the progress of this disease in humans. However, authors are cautious, admitting that they cannot prevent the fragmentation of ataxin-3 totally. The fact that it could be slowed down enough to prevent the disease from arising during people's life seems to be an incredible victory over this terrible disease. If these results prove to be valid in humans, the next step then will be to develop drugs capable of blocking calpain. There is still much to learn about this disorder as there are surely more pieces to this puzzle, but it seems as though there may be a light at the end of the tunnel.