A Genomic Screen for Modifiers of Tauopathy Identifies Puromycin-Sensitive Aminopeptidase as an Inhibitor of Tau-Induced Neurodegeneration

Neurofibrillary tangles (NFT) containing tau are a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD). NFT burden correlates with cognitive decline and neurodegeneration in AD. However, little is known about mechanisms that protect against tau-induced neurodegeneration....

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2006-09, Vol.51 (5), p.549-560
Main Authors: Karsten, Stanislav L., Sang, Tzu-Kang, Gehman, Lauren T., Chatterjee, Shreyasi, Liu, Jiankai, Lawless, George M., Sengupta, Soma, Berry, Robert W., Pomakian, Justine, Oh, Hyun S., Schulz, Cordula, Hui, Koon-Sea, Wiedau-Pazos, Martina, Vinters, Harry V., Binder, Lester I., Geschwind, Daniel H., Jackson, George R.
Format: Article
Language:English
Subjects:
Aminopeptidases - metabolism
Animals
Blotting, Northern
Blotting, Western
Brain - enzymology
Brain - pathology
Drosophila
Gene Expression Profiling
Humans
HUMDISEASE
Immunohistochemistry
In Situ Hybridization
Mice
Mice, Transgenic
MOLNEURO
Nerve Degeneration - enzymology
Nerve Degeneration - pathology
Neurofibrillary Tangles - enzymology
Neurofibrillary Tangles - pathology
Oligonucleotide Array Sequence Analysis
tau Proteins - genetics
tau Proteins - metabolism
Tauopathies - enzymology
Tauopathies - genetics
Tauopathies - pathology
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Summary:Neurofibrillary tangles (NFT) containing tau are a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD). NFT burden correlates with cognitive decline and neurodegeneration in AD. However, little is known about mechanisms that protect against tau-induced neurodegeneration. We used a cross species functional genomic approach to analyze gene expression in multiple brain regions in mouse, in parallel with validation in Drosophila, to identify tau modifiers, including the highly conserved protein puromycin-sensitive aminopeptidase (PSA/Npepps). PSA protected against tau-induced neurodegeneration in vivo, whereas PSA loss of function exacerbated neurodegeneration. We further show that human PSA directly proteolyzes tau in vitro. These data highlight the utility of using both evolutionarily distant species for genetic screening and functional assessment to identify modifiers of neurodegeneration. Further investigation is warranted in defining the role of PSA and other genes identified here as potential therapeutic targets in tauopathy.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2006.07.019