Huntington's disease is an inherited neurodegenerative disorder which leads to the progressive deterioration of movement, cognition and behavior. In the US, 30,000 people are living with Huntington's disease, and another 200,000 individuals are at risk, where symptoms can start at any point between childhood to advanced age. While approaches such as speech and physical therapy, antidepressants and antipsychotics have been adopted to slowing down disease progression, there is currently no approved treatment for the reversal of the disease. Recently, a drug has entered clinical trials and results are awaited with bated breath.
In the human body, misfolded or dysfunctional proteins are engulfed by structures called autophagosomes, which target such proteins for degradation via a pathway called autophagy. Here, Huntington's disease is caused by a mutation in the HTT gene, which encodes a protein called Huntingtin (HTT). This mutation allows the HTT protein to escape autophagy, and instead accumulate and destroy neuronal cells found in the brain over a period of 10-25 years.
In a recent study published in Nature, researchers have identified four synthetic organic compounds which link the mutant HTT to a protein called LC3 which is present on autophagosomes, thereby ensuring the removal of the mutant HTT by autophagy.
These four compounds lowered the levels of the mutant HTT protein by approximately 30% in comparison to normal HTT, when tested in different mediums — specifically in vivo in Drosophila fly and mice models of Huntington's disease, and in vitro on cultured neuronal cells obtained from mice and individuals with Huntington's disease.
In addition, these compounds are specific for the mutated portion of the Huntingtin protein as they could potentially attack another similarly mutated protein called Ataxin-3, which happens to cause spinocerebellar ataxia — an incurable neurodegenerative disease. The compounds were even capable of reversing the disease symptoms in both Drosophila flies and mice. Here, the affected flies and mice on treatment with the compounds displayed significant improvement in behavioral and movement deficits measured by tests such as whether the Drosophila could fly, and how well mice were able to balance and display gripping force.
These four synthetic compounds serve as promising candidates for future drug discovery research in this field. The study also opens the field for targeting several proteins which accumulate the same kind of mutation, leading to severe neurodegenerative disorders.