A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration.

Authors: Karsten SL; Sang TK; Gehman LT; Chatterjee S; Liu J; Lawless GM; Sengupta S; Berry RW; Pomakian J; Oh HS; Schulz C; Hui KS; Wiedau-Pazos M; Vinters HV; Binder LI; Geschwind DH; Jackson GR

Abstract: 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.

Keywords: Aminopeptidases/*metabolism; Animals; Blotting, Northern; Blotting, Western; Brain/*enzymology/pathology; Drosophila; Gene Expression Profiling; Humans; Immunohistochemistry; In Situ Hybridization; Mice; Mice, Transgenic; Nerve Degeneration/*enzymology/pathology; Neurofibrillary Tangles/enzymology/pathology; Oligonucleotide Array Sequence Analysis; Tauopathies/enzymology/*genetics/pathology; tau Proteins/genetics/*metabolism
Journal: Neuron
Volume: 51
Issue: 5
Pages: 549-60
Date: Sept. 5, 2006
PMID: 16950154
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Citation:

Karsten SL, Sang TK, Gehman LT, Chatterjee S, Liu J, Lawless GM, Sengupta S, Berry RW, Pomakian J, Oh HS, Schulz C, Hui KS, Wiedau-Pazos M, Vinters HV, Binder LI, Geschwind DH, Jackson GR (2006) A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration. Neuron 51: 549-60.


Lifespan Factors:
  • Psa Puromycin sensitive aminopeptidase


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