Compound that aids in the digestion of fatty foods within the intestine demonstrates potential as a treatment for a rare brain disorder

In a work, recently published in the Journal of Clinical Investigation, researchers at the Life and Health Science Research Institute (ICVS) at the University of Minho, in Portugal, used animal models of spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3/MJD) to test a promising drug: the compound tauroursodeoxycholic acid (TUDCA for short). They concluded that TUDCA was able to stop the progression of motor symptoms and improve several abnormalities of neurons and other brain cells that are typical of this disease.

This included reduced brain inflammation, reduced signs of degeneration, and an overall increased survival of neurons. Interestingly, when testing in mice, all of these changes were seen both when TUDCA was supplemented in the food, or directly injected. This is important since SCA3/MJD is a chronic, long-term disorder, for which treatment using tablets is much preferable.

TUDCA is a well-known bile acid. After being produced in the liver and released to the gut, bile acids work as “detergents”to help emulsify and facilitate absorption of dietary fats. However, they also seem to play a signalling role in the brain, although far less clear. Previous research has shown that bile acids such as TUDCA are able to reduce inflammation and the death of neurons in the brain. In fact, TUDCA has been tested as a potential treatment for several neurological diseases such as Alzheimer’s and Parkinson’s disease, even reaching clinical trials. However, this is the first time that it was tested in the rare inherited neurodegenerative disorder known as spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3/MJD). This severe condition usually starts manifesting in mid-adulthood, and patients develop progressive motor symptoms such as imbalance (named ataxia), lack of coordination and difficulties in speaking and swallowing, that are very limiting. There are no effective treatments for SCA3/MJD, leaving patients only with options for a partial and transient symptomatic relief.

Given that the mechanisms through which bile acids have their effects in the brain is not fully understood, researchers have also delved into this matter, and found that TUDCA was working in a very different manner than expected. TUDCA was found to exert its effect by interacting not with its classically known receptor, but with a protein named glucocorticoid receptor (GR). This receptor is essential as an effector for steroids (molecules derived from cholesterol, with some structural resemblance to TUDCA), but it was previously unknown to bind to bile acids in animals. In the study, researchers found that blocking GR from functioning also stopped TUDCA from having an effect in the disorder. Surprisingly, and coming full circle, it was also observed that, inside the brain cells of SCA3/MJD mice, the GR is likely being excessively destroyed by protein degrading molecular machines known as proteasomes, and that TUDCA protects it from this degradation.

While this work is not a clinical trial (meaning that TUDCA was not tested in patients), researchers found evidence of GR malfunction in both the brain and the blood of SCA3 patients, which is in line with the animal data. This suggests that TUDCA may also work in patients, such as it worked in animal models. Moreover, TUDCA is itself a great candidate for a clinical trial, as it is well-known to be safe with long-term use, and with little side effects. This study sheds light on a possible novel therapeutic option for SCA3/MJD patients, and it is a breakthrough on a possible drug target for the development of novel pharmaceuticals, bringing new hope for the families affected by this disease.