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2016 Grants - La Spada
Modulators of Transcription Factor EB (TFEB)
Albert La Spada, M.D., Ph.D.
University of California, San Diego
La Jolla, California
2016 Collaboration 4 Cure (C4C)
Can novel drug candidates that help regulate the removal of abnormal proteins be potential Alzheimer’s disease treatments?
In cells, unusable or damaged proteins are broken down through a process called “autophagy.” Proteins are transported through several compartments within the cell where the damaged cargo can be recycled or destroyed. In Alzheimer’s disease this process is disrupted, which can lead to the harmful accumulation of beta-amyloid and abnormal tau, which are the proteins that build up in the Alzheimer’s brain to form plaques and tangles, respectively.
Recent evidence suggests a protein called Transcription Factor EB (TFEB) may be a key regulator of autophagy. The TFEB protein binds to and activates certain genes that are important for the process of clearing unwanted proteins from cells. By binding to these genes, TFEB helps regulate autophagy processes as needed. Previous studies in animals have shown that an increase in levels of TFEB can enhance the clearance of abnormal proteins from the brain and help improve cognition. However, little is known about how TFEB itself is regulated or the role it may play in Alzheimer’s disease.
Albert La Spada, M.D., Ph.D. and colleagues have developed a tool to identify novel compounds which may modulate expression of the TFEB gene which codes for the TFEB protein. Using nerve cells grown in laboratory dishes they will “screen” thousands of these compounds to find those that increase the level of TFEB. They will generate a library of novel drug compounds and investigate how the most potent of these compounds affect the autophagy process and the removal of abnormal proteins in nerve cells.
The novel compounds identified in these studies may help to regulate protein clearance and contribute to more effective removal of beta-amyloid and abnormal tau from the brain. Ultimately these drug candidates could serve as potential treatments to slow, halt or prevent Alzheimer’s disease.