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 vitrostructural 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.
M.W. Rousseaux, M. De Haro, C.A. Lasagna-Reeves, A. De Maio, J. Park, I, Al-Ramahi, N. Lu, A. Sharma, L. Vilanova-Velez, T.F. Westbrook, J.C. Troncoso, R. Kayed, J. Botas, H.Y. Zoghbi. TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau. Elife 2016 Oct 25;5.
C.A Lasagna-Reeves, M. De Haro, S. Hao, J. Park, M.W.C. Rousseaux, I. Al-Ramahi, P. Jafar-Nejad, L. Vilanova-Velez, L. See, A. De Maio, Z. Wu, J.C. Troncoso, T.F. Westbrook, J. Tang,J. Botas, H.Y. Zoghbi. Reduction of Nuak1 decreases tau and reverses symptoms in a tauopathy mouse model. Neuron 2016 Oct 19;92(2):407-418.
Subject of a Neuron Preview commentary by S. Maeda and L. Mucke., 2016 Oct 19;92(2):265-267.
Subject of a Science Signaling Editors’ Choice by Leslie K. Ferrareli., 2016 Oct 9;45: ec252. Featured at Alzforum: http://www.alzforum.org/news/research-news/new-target-tauopathies-blocking-nuak1-could-reduce-tau-build
C.A. Lasagna-Reeves, M.W.C. Rousseaux, M.J. Guerrero-Munoz, L. Vilanova-Velez, J. Park, L. See, P. Jafar-Nejad, R.Richaman, H.T. Orr, R. Kayed and H.Y. Zoghbi. ATAXIN-1 oligomers induce local spread of pathology and decreasing them by passive immunization slowls Spinocerebellar ataxia type 1 phenotypes. Elife 2015 December 17;4
C.A. Lasagna-Reeves, M.W.C. Rousseaux, M.J. Guerrero-Munoz, J. Park, R.Richaman, N. Lu, U. Sengupta, A. Litvinchuk, H.T. Orr, R. Kayed and H.Y. Zoghbi. A native interactor scaffolds and stabilizes toxic ATXIN-1 oligomers in SCA1. Elife. 2015 May 19;4.
- Sengupta, M.J. Guerrero-Munoz, D. L. Castillo-Carranza, C.A. Lasagna-Reeves, J.E. Gerson, G.R. Jackson and R. Kayed. Synergistic toxicity of oligomeric α-synuclein and tau in synucleinopathies. Biol Psychiatry. 2015 Jan 9. Subject of a Biological Psychiatric editorial commentary by Delenclos, M. Moussaud, S. and McLean, P.J., 2015 Nov 15;78(10):666-7.
C.A. Lasagna-Reeves, D.L. Castillo-Carranza, U. Sengupta, J.E. Gerson, M.J. Guerrero-Munoz, J.C. Troncoso, G.R. Jackson and R. Kayed. The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotype. Acta Neuropathol Commun. 2014 May 29;2:56.
D.L. Castillo-Carranza, U. Sengupta, M.J. Guerrero-Munoz, C.A. Lasagna-Reeves, J.E. Gerson, G. Singh, D.M. Estes, A.D. Barrett, K.T. Dineley, J.R. Jackson and R. Kayed. Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci. 2014 Mar 19;34(12):4260-72.
Kayed and C.A. Lasagna-Reeves. Molecular Mechanism of Amyloid Oligomers Toxicity, J Alzheimer’s Dis. 2013 Jan 1;33(0):S67-78.
C.A. Lasagna-Reeves, D.L. Castillo-Carranza, U. Sengupta, M.J. Guerrero-Munoz, T. Kiritoshi, V. Neugebauer, G.R. Jackson, R. Kayed. Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau, Sci Rep. 2012;2:700.
C.A. Lasagna-Reeves, D. L. Castillo-Carranza, U. Sengupta, J. Sarmiento, J. Troncoso, G.R. Jackson and R. Kayed. Identification of oligomers at early stages of tau aggregation in Alzheimer’s disease, FASEB J, 2012 May;26(5):1946-59.
Faculty Research Team
Additional Research Team Members
Other research team members include Yingjian You (Research Analyst) and Abigail Perkins (Research Technician).