Dr. Judith Steen
Title: Single-Cell to Clinical Applications of Proteomics in Neurodegenerative Diseases
Bio:
Dr. Judith Steen is a Professor of Neurology at Harvard Medical School, the Director of the Neuroproteomics Laboratory in the F.M. Kirby Center for Neurobiology at Boston Children’s Hospital, and a member of the Harvard Stem Cell Institute (HSCI). She pioneered innovative mass spectrometry-based proteomic approaches to understand neurodegenerative diseases, focusing on how central and peripheral nervous system cells are born, maintained, and die. Her laboratory has developed groundbreaking technologies, including the FLEXITau platform, which enables the comprehensive quantification of tau protein post-translational modifications (PTMs), revealing critical stages of Alzheimer’s disease and patient heterogeneity, as published in Cell and Nature Medicine. Her landmark studies provided the first comprehensive maps of human tau modifications, defining the molecular structures of tau prions and correlating specific post-translational modifications (PTMs) with disease progression. These studies were also the first to reveal that pT217 is the earliest key differentiator of healthy vs Alzheimer’s disease patients. Dr. Steen’s work extends beyond tau pathology to include novel proteogenomic methods that identify non-canonical translation products under neuronal stress, as well as systems biology approaches that reveal master regulators for neuronal regeneration after injury. Through sophisticated quantitative proteogenomic and computational biology approaches, the Steen lab dissects how genetics, infection, excitotoxicity, injury, and aging contribute to neurodegeneration, and why specific CNS cells show greater vulnerability than others. Her contributions have significantly advanced our understanding of neurodegenerative mechanisms and opened new avenues for diagnostic and therapeutic interventions.
Abstract:
Neurodegenerative diseases, including Alzheimer’s, Frontotemporal Degeneration, Parkinson’s, and ALS, share a defining pathology: the abnormal aggregation of proteins such as tau, TDP-43, and alpha-synuclein. Yet, the molecular mechanisms driving the tipping point where functional proteins become toxic, triggering neuronal dysfunction and death, remain poorly understood. Further, the pathways and specific chemical changes were unclear.
To address this challenge, we developed the FLEXIQuant Platform, a next-generation mass spectrometry-based proteomics approach that offers unmatched sensitivity and specificity for profiling disease-associated protein modifications and mapping the changes in the global pathways during disease progression. FLEXIQuant enables high-resolution mapping of post-translational modifications on pathological aggregates from human patients and animal models, across disease progression timelines.
By decoding these molecular fingerprints in large patient cohorts, we’ve uncovered: 1) Distinct modification patterns that define disease stages and patient subtypes, 2) Predictive signatures linked to clinical trajectories, 3) Sequential tau modifications that drive aggregation and inter-neuronal spread in Alzheimer’s. These insights enable us to distinguish pathological protein species from their healthy counterparts, unlocking new therapeutic strategies that selectively target disease-driving forms while preserving physiological function.
This talk will explore how technological advancements in quantitative proteomics are transforming our understanding of neurodegeneration, with further insights into co-pathology in neurodegeneration and differentiation between disease groups with similar clinical phenotypes. Finally, we will cover future directions regarding single-cell resolution, large-scale platforms for clinical translation, and how proteomics will inform biological mechanisms, early diagnosis, and precision therapeutics.
Keywords: Mass Spectrometry, Proteomics, Single Cell
Host: Prof. Lloyd Smith