The research lab of Dr. Lasagna-Reeves focuses on the role protein tau plays in neurodegenerative diseases.
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’s disease and more than 20 other neurodegenerative tauopathies. Therefore, the study of the physiological and pathological function of tau is key to understanding and treating these neurodegenerative diseases. Hence, the main focus of the Lasagna-Reeves Lab is to comprehensively elucidate the role that tau physiology plays in neurodegenerative tauopathies.
Role of Tau Native Interactors on Tau Amyloidogenic Properties and Disease Pathogenesis
The Lasagna-Reeves Lab studies the role of different physiological partners of tau in its stabilization, accumulation, localization, folding, misfolding and toxicity. To pursue this, the lab combined in vitro structural and cellular techniques with mouse genetic and pharmacological manipulations to determine the effects of a specific interactor on tau toxicity in neurodegenerative tauopathies. This research strategy is suitable for tau and 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 Impact on 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 soluble tau levels is most critical. It was previously demonstrated how reducing the levels of Nuak1, an AMPK-related kinase, decreases tau and reverses phenotypes in a tauopathy mouse model (C.A. Lasagna-Reeves, Neuron, 2016). The Lasagna-Reeves Lab continues to dissect 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, it was 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 the Lasagna-Reeves Lab is studying the role of tau in the plasma membrane and dissecting the mechanism of APFs formation.
NIH/NINDS 1K22NS092688-01 Studying the Physiological Role of Nuak1 in Tau Pathogenesis Role: PI 07/01/2015-06/30/2020