title: A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration.
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.
authors.affiliation: Program in Neurogenetics, Department of Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Stanislav L
authors.initials: SL
authors.lastname: Karsten
authors.forename: Tzu-Kang
authors.initials: TK
authors.lastname: Sang
authors.forename: Lauren T
authors.initials: LT
authors.lastname: Gehman
authors.forename: Shreyasi
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Jiankai
authors.initials: J
authors.lastname: Liu
authors.forename: George M
authors.initials: GM
authors.lastname: Lawless
authors.forename: Soma
authors.initials: S
authors.lastname: Sengupta
authors.forename: Robert W
authors.initials: RW
authors.lastname: Berry
authors.forename: Justine
authors.initials: J
authors.lastname: Pomakian
authors.forename: Hyun S
authors.initials: HS
authors.lastname: Oh
authors.forename: Cordula
authors.initials: C
authors.lastname: Schulz
authors.forename: Koon-Sea
authors.initials: KS
authors.lastname: Hui
authors.forename: Martina
authors.initials: M
authors.lastname: Wiedau-Pazos
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Lester I
authors.initials: LI
authors.lastname: Binder
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: George R
authors.initials: GR
authors.lastname: Jackson
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D004330:Drosophila; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000201:enzymology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D024801:Tauopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme