Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

Autor: Jennifer Rodriguez-Rivera, Shon A. Koren, Moriel H. Vandsburger, Tal Frolinger, Anika M.S. Hartz, Fabio Di Domenico, Emad Chishti, Chiara Lanzillotta, Ryan Cloyd, Jeffrey M. Axten, Matthew Hamm, Duc M. Duong, Alexandria Ingram, Nicholas Zulia, Nicholas J. Laping, Sarah N. Fontaine, John Koren, David K. Powell, Sara Galvis-Escobar, Nicholas T. Seyfried, Jose F. Abisambra, Michelle C. Bell
Jazyk: angličtina
Rok vydání: 2021
Předmět:
GSK2606414
MEMRI
TMT proteomics
kinases
tau
animals
brain
disease models
animal
hippocampus
humans
mice
mice
transgenic
neurodegenerative diseases
neurons
phosphorylation
protein kinase inhibitors
proteome
proteomics
severity of illness index
tauopathies
unfolded protein response
eIF-2 kinase
tau proteins
Proteomics
Proteome
Hippocampus
Severity of Illness Index
lcsh:Chemistry
Mice
eIF-2 Kinase
Phosphorylation
Cognitive decline
lcsh:QH301-705.5
Spectroscopy
Neurons
Kinase
Brain
Neurodegenerative Diseases
General Medicine
Computer Science Applications
Tauopathies
Tauopathy
Quantitative proteomics
Mice
Transgenic
tau Proteins
Article
Catalysis
Inorganic Chemistry
Atrophy
medicine
Animals
Humans
Physical and Theoretical Chemistry
Protein Kinase Inhibitors
Molecular Biology
Mechanism (biology)
business.industry
Organic Chemistry
medicine.disease
Disease Models
Animal
lcsh:Biology (General)
lcsh:QD1-999
Unfolded Protein Response
business
Neuroscience
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 1186, p 1186 (2021)
International Journal of Molecular Sciences
Volume 22
Issue 3
ISSN: 1661-6596
1422-0067
Popis: Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer&rsquo
s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.
Databáze: OpenAIRE
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