University of California, Santa Barbara researchers have made significant progress in understanding the molecular mechanisms underlying a spectrum of neurodegenerative diseases, including frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration. These conditions are characterized by the accumulation of abnormal, misfolded tau proteins in the brain, which can lead to the formation of neurofibrillary tangles and the subsequent disruption of brain function.
The team identified potential ways to interrupt this process by targeting "sticky" sites along the long form of mutated tau, preventing the misfolding and spreading of the neurofibrillary tangles. This interdisciplinary collaboration provided molecular-level insights into the way pathological tau spreads, which could pave the way for the development of therapeutic interventions capable of disaggregating tau or preventing its aggregation.
According to the study, published in PNAS, tau, an essential structural protein in the brain, can mutate and misfold, becoming sticky and tangled. This error in folding can then serve as a template for the misfolding of normal tau proteins, leading to the accumulation of neurofibrillary tangles in specific regions of the brain, depending on the type of neurodegenerative disorder.
By using advanced techniques such as transmission electron microscopy and molecular dynamics simulations, combined with in vitro experiments, the research team was able to identify a "sticky hairpin" structure within the longer "four-repeat" version of tau. This hairpin structure contains a segment called PHF6 that can bind and stack up other tau proteins into large aggregations.
The researchers discovered that by inducing tau aggregation in cell culture and targeting the PHF6 region, they were able to prevent tau aggregation. They also found that nanobodies, which are fragments of antibodies derived from camelids, were able to bind to the PHF6 region and inhibit the aggregation of tau.
While there is still a long way to go before targeted therapeutics can be developed and approved, these findings provide exciting potential pathways for arresting the critical steps toward the accumulation of mutant tau in neurodegenerative diseases. The researchers plan to continue testing their findings in animal models and exploring the potential application of their discoveries to more complex forms of neurodegenerative diseases, such as Alzheimer's disease.