Cryo-EM reveals TAF15 as potential treatment target for frontotemporal dementia

An international team of researchers, including experts at the Indiana University School of Medicine, has identified a protein found in the brains of people with frontotemporal dementia (FTD), discovering a new target for potential treatments for the disease.

According to the National Institutes of Health, FTD results from damage to neurons in the frontal and temporal lobes of the brain. People with this type of dementia usually show symptoms, such as unusual behaviours, emotional problems, problems communicating, difficulty working or in some cases difficulty walking, between the ages of 25 and 65.

Neurodegenerative disorders, including dementia and amyotrophic lateral sclerosis (ALS), occur when certain proteins form amyloid filaments in nerve cells in the brain and spinal cord. The multidisciplinary team of researchers—including members from the Medical Research Council (MRC) Molecular Biology Laboratory, the IU School of Medicine and the University College London Queen Square Institute of Neurology—found that in cases of FTD, a protein called TAF15 forms these filaments amyloid in brain and spinal cord cells. On December 6, they published their findings in the Nature.

Bernardino Ghetti, MD is a distinguished professor at the IU School of Medicine and has been studying neurodegenerative dementias for 50 years. As the lead neuropathologist on the project, Ghetti and his team studied protein aggregates from brains donated by four people who had frontotemporal dementia and motor weakness. Together with their UK colleagues, IU researchers used neuropathological and molecular techniques and state-of-the-art cryo-electron microscopy (cryo-EM) at individual resolution to discover the presence of amyloid filaments from TAF15 protein in multiple regions of the brain. However, it is important to note that TAF15 amyloid also affects motor nerve cells.

This discovery represents a breakthrough that identifies TAF15 as a potential target for developing diagnostic and therapeutic strategies towards a lesser-known form of frontotemporal lobar degeneration associated with frontotemporal dementia.”

Bernardino Ghetti, MD, Distinguished Professor, IU School of Medicine

Additional authors on the study are Stephan Tetter of the MRC Laboratory of Molecular Biology, Diana Arseni, Alexey G. Murzin, Sew Y. Peak-Chew and Benjamin Ryskeldi-Falcon. Yazead Buhidma and Tammaryn Lashley of University College London. and the IU School of Medicine’s Holly J. Garringer, Kathy L. Newell, Ruben Vidal and Liana G. Apostolova.

The study was funded in part by the National Institute on Aging and the NIH National Institute of Neurological Disorders and Stroke.