Neuron. 2006 Sep 7;51(5):549-60.A genomic screen for
modifiers of tauopathy identifies puromycin-sensitive
aminopeptidase as an inhibitor of tau-induced neurodegeneration.
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.
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.
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.
PMID: 16950154 |
