Study Finds Key Brain Protein May Have Role in Psychiatric Disorders

By Arshia Leekha

10 December 2021

Neuroscientists have made great strides in shedding light on the complexities of the human brain, but our grey matter still holds a great many mysteries when it comes to understanding brain function at the molecular level.  Now, a new study from the Department of Molecular and Cellular Biology has revealed that a unique protein critical to multiple cellular processes in the brain may also be linked to the development of psychiatric disorders like schizophrenia. 

“The ‘Arc’ protein is a key player of neuroplasticity in our nervous system,” says Dr. Jasmin Lalonde, who oversaw the study.  “As such, it plays an important role in memory formation and other brain processes as well.”

What makes this protein so interesting, says Lalonde, is that it bears striking similarities to viral proteins, including the one found in HIV.  Not only that, Arc can also assemble into a viral structure known as a capsid that can transfer genetic material from one brain cell (neuron) to another. 

The unique properties of Arc and its multifaceted role in brain cell function have long intrigued researchers, including Lalonde, who first began studying Arc during his post-doctoral research in Boston.

“We know a lot about the different roles of Arc, but what we still don’t really understand is how these different roles are coordinated within the cell,” says Lalonde.

Lalonde had previously discovered that Arc proteins undergo certain modifications after they are produced, which changes the function of the protein.  Suspecting that other types of modification may further explain how Arc plays such diverse roles in the brain, Lalonde and PhD student Alicyia Walczyk-Mooradally decided to search for additional ways the molecular structure of the protein may be altered by the cell.    

Working with colleagues at both the University of Guelph and in the United States, the team’s search led to an unexpected connection between Arc and another protein known as “TNIK”.  TNIK is an enzyme important for communication between neurons. When they investigated this novel connection more closely, they found that TNIK modified Arc by adding phosphate molecules to two specific locations on the protein.

“This is the first time Arc and TNIK have ever been linked together,” says Lalonde.

Walczyk-Mooradally took the findings one step further by generating Arc proteins with mutations at each of the sites normally phosphorylated by TNIK. These mutants confirmed that TNIK modification strongly influences the structure and distribution of Arc in the brain, and even its ability to form a capsid.

What makes the team’s findings even more interesting is that uncontrolled TNIK activity is implicated in several neuropsychiatric disorders such as Alzheimer’s, epilepsy, chronic pain, schizophrenia, Parkinson’s disease, and others.

This means that the interplay between TNIK and Arc and its downstream effects on Arc function could be contributing to the onset and progression of several brain disorders.  Revealing the link between these two proteins in various diseases will be an important topic for future research efforts.

“The more we understand brain function and dysfunction at the molecular level, the better equipped we are to identify new treatment targets for devastating neurodegenerative diseases,” says Lalonde. 

This study was funded by the Natural Sciences and Engineering Research Council.  

Read the full study in the Journal of Neurochemistry.

Read about other CBS Research Highlights.