Faculty Member
Assistant Professor
Department of Neurology
David Geffen School of Medicine
University of California, Los Angeles
Personal Statement
Accurate protein folding is essential for cellular function. Protein misfolding and aggregation is implicated in widespread diseases. My lab applies biophysical, biochemical, and systems genetics techniques to characterize how cells control protein aggregation and find novel targets for protein aggregation diseases.
As a graduate student in Susan Marqusee’s Lab at UC Berkeley, I created new technologies to probe the fundamental biophysical properties of proteins in physiological contexts. Current quantitative descriptions of protein behavior are derived from experiments in the test tube that do not recapitulate fundamental aspects of cell biology, such as protein translation. I created new technologies to probe how translation alters the biophysical properties of the emerging nascent chain. I discovered that translation changes the folding stability (∆Gfolding) and kinetics of the nascent chain (Samelson et al. PNAS 2016, Jensen, Samelson et al. JBC 2020), and that translation can fundamentally alter a protein’s folding pathway to avoid aggregation (Samelson et al. Science Advances 2018). These works highlight the importance of taking the cellular environment into account when studying protein folding and aggregation.
As a postdoc in Martin Kampmann’s Lab at UCSF, I extended this paradigm to protein aggregation in disease. I took an unbiased approach to finding cellular factors that control protein aggregation in human neurons. Aggregation of the protein tau is hallmark of many neurodegenerative diseases, including Alzheimer’s disease. Tau aggregates in disease-specific aggregate structures and patterns of spread in the brain. This strongly suggests that disease-causing perturbations to the cellular environment also exert conformational control that results in disease-specific tau aggregate structures. I established a CRISPR-based screening platform in iPSCderived neurons to systematically identify genetic modifiers of tau aggregation. I discovered a new tau E3 ubiquitin ligase, CRL5SOCS4 , and discovered how oxidative stress causes accumulation of a tau cleavage fragment that alters tau aggregation in vitro. My work highlights the power of using disease-relevant cell types as discovery tools to reveal disease mechanisms.
My independent research focuses on characterizing the conformational states a protein populates en route to its final aggregate state, a protein’s aggregation trajectory, and how cell types vulnerable to aggregation control that trajectory. My goal is to identify novel mechanisms that are therapeutic targets for neurodegeneration.
