Investigating the tau-Fyn interaction in normal and diseased states of the brain

Neurodegenerative diseases are debilitating conditions characterized by a progressive decline in memory that ultimately results in dementia. Alzheimer’s disease (AD) is the most common and most well-known. AD, along with a subset of disorders such as frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTPD-17) are also collectively known as tauopathies, because the patients’ brains commonly contain tangles made up of an abnormally folded protein called tau. However, tau does not act alone in causing disease. It interacts with a host of other proteins and has diverse functions. One of these proteins that also interact with tau is Fyn, a kinase that acts as an on/off switch for a variety of cellular functions. However, what does the tau-Fyn interaction do in both normal and diseased states of the brain are still unknown.

Our lab found that if you remove both tau and Fyn from a healty mouse, the mouse experienced memory problems and their neurons had reduced influx of calcium when stimulated. In an FTDP-17 disease mouse model, we found that when we removed Fyn, the mouse was prevented from mutant tau induced memory problems and had reduced tau hyperphosphorylation, a hallmark of neurodegeneration. Lastly, we found that in AD brains, Fyn mediated phosphorylation at Tyr-tau is differentially regulated from Ser/Thr-tau, indicating that Fyn phosphorylation of tau at Y18 may serve a different function than Ser/Thr phosphorylation. Together, these findings provide further evidence for the role of tau and Fyn functions in the neurodegenerative process and may lead to the design of novel therapeutics targeting this interaction to treat AD and FTDP and other related dementias.