Scientists from Scripps Florida have identified a number of new therapeutic targets for memory disorders and developed a new screening test to uncover compounds that may one day work against those disorders. Two studies, both led by TSRI biologist Sathyanarayanan V. Puthanveettil, could lead to new approaches to treating some of the most problematic diseases facing a rapidly aging global population, including Alzheimer's disease, Huntington's disease, and dementia.
TSRI Assistant Professor Sathyanarayanan V. Puthanveettil
“We are actively looking at molecules critical to memory formation, so these two studies work in parallel,” said Dr. Puthanveettil. “In one study, we're reaching for a basic understanding of the process, and in the other, we're finding new ways to identify drug candidates so that we can cure these diseases.”
One of the studies provides a detailed description of the proteins that are transported to the synapses, which are collectively called the “synaptic proteome.” Synapses are the part of a nerve cell (neuron) that pass electrochemical signals to other cells during functions such as memory storage. This new approach has the potential to advance our understanding of how synapses work, how their composition changes with learning, and how brain diseases might affect them.
“We know these molecules function in the synapse, and if we can regulate their function, there may be some very good therapeutic opportunities,” said Dr. Puthanveettil.
The study focuses on kinesin, a molecular motor protein that plays a role in the transport of other proteins throughout a cell. Analyzing three kinesin complexes, the researchers found that approximately half of kinesins' cargo are synaptic proteins – and that the identity and location of these kinesins determine which proteins they transport. These results reveal a previously underappreciated role of kinesins in regulating the composition of the entire synaptic proteome.
Interestingly, analysis revealed the three kinesin cargo complexes examined in the study are involved in neurologic diseases. Approximately 60 cargos (out of 155) of the kinesin Kif5C are implicated in psychiatric disorders, while around 20 cargos of kinesin Kif3A are implicated in developmental disorders.
“This shows for the first time how kinesins expressed in the same neurons can carry substantially different cargos,” said Research Associate Xin-An Liu, the first author of the study. “We can use this approach to identify what molecules may be targeted for memory and in major disorders. The next step is to find how the synaptic proteome changes in neuropsychiatric diseases.”
In the second study, Dr. Puthanveettil and his colleagues began exploring how their new high-throughput screening test could help discover potential drug candidates to treat memory disorders that are based on kinesin and axonal transport. “The luminescence-based assay that we developed is highly reproducible and robust,” said Dr. Puthanveetil.
Using the approach, the team screened a compound collection and identified a number of small molecules that turned on or off the activity of a human kinesin.