Su Yang, Ph.D., from Emory University in Atlanta is one of the National Ataxia Foundation postdoctoral fellowship recipients of 2016 for the project titled “Developing the MANF-based therapeutic approach for Spinocerebellar Ataxia 17.”
Spinocerebellar Ataxia 17 (SCA17) is an inherited condition characterized by a gradual loss of neuronal functionality associated with locomotion, muscle coordination, eye movements, and speech. This induces a broad spectrum of symptoms associated with disorders like Parkinson’s, ataxia, and dementia.
SCA17 is caused by a particular mutation in a gene encoding a protein called TATA box binding protein (TBP), involved in regulating the activity of genes of most body cells and tissues. The TBP normally links to a specific sequence of DNA known as the TATA box. After binding, the complex becomes responsible for guiding gene reading enzymes that transfer the information in a process called mRNA transcription. In SCA17, the defective gene induces a misfolding in the TBP and becomes toxic.
There are no effective therapies for SCA17, and most of the available drugs are designed to relieve symptoms rather than to stop the irreversible progression of the disease. Through this fellowship, Yang will investigate novel therapeutic approaches for treating SCA17.
Previous studies by Yang’s affiliated research group identified a promising therapeutic route. The team found that a protein called mesencephalic astrocyte-derived neurotrophic factor (MANF) is modestly expressed in the cerebellum of a mouse model of SCA17, and when its levels are increased there is an improvement in SCA17 disease phenotypes, indicating MANF as a promising therapeutic target for SCA17 treatment.
The team examined a set of compounds, including naturally-based ones, approved by the U.S. FDA. They identified a number of them with the properties to activate the expression of MANF in vitro in cultured cells.
During this fellowship, Yang and colleagues will continue to test these compounds in vivo in a mouse model of SCA17. Since the compounds are already authorized by the FDA, the results would immediately impact the development of therapeutic targets to treat SCA17.
The findings are also expected to have broad significance for the treatment of other types of SCA, as well as related disease like Parkinson’s and ischemic stroke.