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. 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.
Karsten
Stanislav L
SL
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.
Sang
Tzu-Kang
TK
Gehman
Lauren T
LT
Chatterjee
Shreyasi
S
Liu
Jiankai
J
Lawless
George M
GM
Sengupta
Soma
S
Berry
Robert W
RW
Pomakian
Justine
J
Oh
Hyun S
HS
Schulz
Cordula
C
Hui
Koon-Sea
KS
Wiedau-Pazos
Martina
M
Vinters
Harry V
HV
Binder
Lester I
LI
Geschwind
Daniel H
DH
Jackson
George R
GR
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*
D016875:tau Proteins; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme