University of Texas Southwestern Medical Center
Center for Alzheimer's and Neurodegenerative Diseases
Marc Diamond, M.D. is the founding director of the Center for Alzheimer’s and Neurodegenerative Diseases (CAND), a multidisciplinary translational research program. The CAND is part of the Peter O’Donnell Jr. Brain Institute and exemplifies its ideal of uniting scientists with diverse interests to cure brain diseases. Dr. Diamond’s discoveries link common disorders such as Alzheimer’s disease to rare infectious prion disorders such as Creutzfeldt-Jakob disease. This has transformed our understanding of why neurogenerative diseases progress, and how different diseases arise. His lab has discovered that abnormal assemblies of the tau protein move between cells and serve as templates for their own replication. Dr. Diamond’s ideas have formed the basis of new therapeutic approaches for Alzheimer’s and related disorders. He holds multiple patents and is the inventor of a monoclonal antibody that is currently in clinical trials. He received his M.D. and residency training in Neurology at UCSF. He was on the faculty at UCSF from 2002-2009, and Washington University in St. Louis from 2009-2014. Since 2014, he has been at UT Southwestern Medical Center. Dr. Diamond is an internationally recognized expert on fundamental mechanisms of neurodegenerative disease. His groundbreaking research has been cited thousands of times by his scientific colleagues.

Moderator of 1 Session

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE: 114

Presenter of 2 Presentations

FUNCTIONAL GENETIC CLASSIFICATION OF ASSEMBLY STRUCTURES IN TAUOPATHIES

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE: 114
Lecture Time
09:10 AM - 09:25 AM

Abstract

Abstract Body

Classification of tauopathies is based on immunohistochemical analyses of brain tissue. Conformations of tau assemblies, or seeds, in tauopathy brain lysate could provide a complementary metric for standard neuropathology. Biosensor cells that express tau repeat domain fused to fluorescent proteins will propagate self-replicating tau assemblies (strains) derived from patient material. Certain strains propagate indefinitely, and produce faithfully transmissible neuropathology upon inoculation into mice. Thus tau can be reasonably considered a mammalian prion. We hypothesize that, as for PrP prions, a “ground truth” of diagnosis in tauopathy could derive from underlying tau assembly conformation, rather than patterns of neuropathology. To build a relatively unbiased classification system, we have created a library of mutants with an alanine scan through the tau repeat domain. Using biosensor cells we have probed assembly of each alanine mutant onto existing stable strains, and onto transient intracellular assemblies induced by exposure to brain lysates. The relative incorporation of alanine mutants into intracellular aggregates is dictated by artificial “species barriers” they create. We thus derive a “fingerprint” of amino acids critical to build a given tau assembly. This unbiased, functional genetic dendrogram of tau prions predicts patterns of neuropathology following inoculation into a tauopathy mouse model. For human brain extracts, this method readily distinguishes different tauopathies. It also implicates amino acids outside the amyloid core defined by cryoEM as critical for stability. In ongoing work we are testing the validity of this structure-based classification scheme.

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