Dr. Anthony Fitzpatrick is an Assistant Professor of Biochemistry and Molecular Biophysics at the Zuckerman Institute, Columbia University, New York, USA. Previously, Anthony was a Marie Curie International Outgoing Fellow at the Laboratory of Molecular
Biology, University of Cambridge (2015–2017) and the California Institute of Technology (2012–2014). He has a biophysics background (PhD with Professor Christopher M. Dobson, University of Cambridge) and undertook postdoctoral training with Professors
Helen Saibil in London, Robert G. Griffin at the Massachusetts Institute of Technology, Ahmed H. Zewail (Nobel Laureate) at the California Institute of Technology and Sjors Scheres and Michel Goedert at the Laboratory of Molecular Biology, Cambridge.
The research focus of the Fitzpatrick Lab is to determine the structure and behavior of patient-derived amyloid fibrils and, more generally, to understand the role of protein aggregation in vivo by identifying the cellular changes that occur in response
to the formation, clearance and spread of fibrillar inclusions. The methods employed by Anthony’s lab are largely experimental and include cryo-electron microscopy (cryo-EM), mass spectrometry, transcriptomics, microfluidics, magic angle spinning
NMR and optical super-resolution microscopy.
Alzheimer’s disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions
comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy
(cryo-EM) maps at 3.4–3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer’s disease. Filament cores are made of two identical protofilaments comprising residues 306–378
of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings
demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.