Cristian A. Lasagna Reeves, PhD
Assistant Professor of Anatomy & Cell Biology
My scientific career has revolved around the study of protein aggregation in neurodegenerative diseases. To investigate the mechanism of these diseases, I have used a broad range of strategies, such as in Vitro aggregation assays with recombinant protein, disease cellular models, mouse genetic interaction experiments, behavioral studies, and human neuropathology. Although I have studied multiple proteins that underlie neurodegenerative disease, my approach has been consistent. I have always been intrigued by the role that native physiological interactors play in the aggregation process of a specific protein. Thus, my overarching goal in my lab is to understand the cellular and molecular mechanisms involved in the transition that a protein undergoes from its physiological function to its aggregated toxic function in neurodegenerative diseases, and the role that native interactors play in this transition.
Titles & Appointments
- Investigator, Stark Neuroscience Research Institute.
Tau Physiology and pathology in neurodegeneration.
Pathological aggregation of the microtubule-associated protein tau and the preponderance of neurofibrillary tangles (NFT) or other inclusions containing tau are the defining histopathological features of Alzheimer disease (AD) and over 20 other neurodegenerative tauopathies. Therefore, the study of the physiological and pathological function of tau is key to understand and treat these neurodegenerative diseases. Hence, the main focus of my lab is to comprehensive elucidated the role that tau physiology plays in neurodegenerative tauopathies.
Investigating the role of tau native interactors on tau amyloidogenic properties and disease pathogenesis.
We study the role of different physiological partners of tau in its stabilization, accumulation, localization, folding, misfolding, and toxicity. To pursue this, we combined in vitro structural and cellular techniques with mouse genetic and pharmacological manipulations to determine the effect of a specific interactor on tau toxicity in neurodegenerative tauopathies. This research strategy is suitable not only for tau, but is also applicable to the study of other neurodegenerative diseases characterized by toxic protein aggregation.
Role of AMPK-related kinases in the pathogenesis of Alzheimer’s disease and how modulation of its levels affects tau-induced pathology.
At the pathological level, the correlation between NFT and disease progression has been studied extensively with conflicting results; the mechanisms linking the pathological aggregation of tau with synaptic dysfunction and neurodegeneration are poorly understood. An emerging view is that NFT themselves are not the true toxic entity in tauopathies, but rather lowering tau levels is most critical. I previously demonstrated how reducing the levels of Nuak1, an AMPK-related kinase, decreases tau a reverses phenotypes in a tauopathy mouse model (C.A. Lasagna-Reeves, Neuron, 2016). Currently in my lab we are continuing dissecting the physiological and pathological relation between AMPK-related kinases and tau.
Formation of tau pore-like structures in neurodegenerative tauopathies.
Annular protofibrils (APFs) represent a new and distinct class of amyloid structures formed by disease- associated proteins. In vitro, these pore-like structures have been implicated in membrane permeabilization and ion homeostasis via pore formation. In previous studies I reported that tau and Aβ APFs are in a pathway distinct from fibril formation in vitro and in vivo. These findings establish the pathological significance of APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative diseases. Currently in the lab we are studying the role of tau in the plasma membrane and dissecting the mechanism of APFs formation.
Desc: Underrepresented Trainee Scholarship to attend to Keystone Symposia “Alzheimer’s Disease – From Fundamental Insights to Light at the End of the Translational Tunnel"
Org: University of Texas Medical Branch
Desc: Dr. and Mrs. Seymour Fisher Academic Excellence Award in Neuroscience
Org: University of Texas Medical Branch
Desc: Jen Chieh and Katherinen Huang Scholarship Award for excellence in Neuroscience
Org: Baylor College of Medicine
Desc: Postdoc Dean’s Award of Excellence