Synthetic replicas of TDP-43 filaments associated with frontotemporal dementia

Case Western Reserve University, Cleveland OH

Investigators

Abstract

The key histopathological feature of frontotemporal lobar degeneration (also known as frontotemporal dementia) and amyotrophic lateral sclerosis is accumulation of aggregated TDP-43 protein in brain. Similar aggregates (filaments) are also associated with a number of other neurodegenerative diseases, including Alzheimer's disease, dementia with Lewy bodies, hippocampal sclerosis and chronic traumatic encephalopathy. An important recent development in the field was determination, by cryo-electron microscopy, of high resolution structures of these TDP-43 filaments derived from brains of individuals afflicted with two different types of frontotemporal lobar degeneration. The overall goal of this exploratory research is to develop and experimental model and establish conditions for generation of amyloid fibrils with structures identical to those of brain-derived filaments from the recombinant TDP-43 in vitro. Upon initial screening by low resolution methods, structural similarity of selected synthetic fibrils to brain-derived filaments will be verified at a high-resolution level by cryo-electron microscopy. Generation of synthetic replicas of TDP-43 filaments associated with different phenotypes of the disease would represent a very important development: it would not only provide a stepping stone for mechanistic studies on disease- relevant TDP-43 aggregation pathways, but also open new avenues for development of drugs (TDP-43 aggregation inhibitors, disaggregating agents) as well as diagnostic tools for early detection of TDP-43 proteinopathies in patients.