TY - JOUR
T1 - Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice
AU - Bustos, Fernando J.
AU - Ampuero, Estibaliz
AU - Jury, Nur
AU - Aguilar, Rodrigo
AU - Falahi, Fahimeh
AU - Toledo, Jorge
AU - Ahumada, Juan
AU - Lata, Jaclyn
AU - Cubillos, Paula
AU - Henríquez, Berta
AU - Guerra, Miguel V.
AU - Stehberg, Jimmy
AU - Neve, Rachael L.
AU - Inestrosa, Nibaldo C.
AU - Wyneken, Ursula
AU - Fuenzalida, Marco
AU - Härtel, Steffen
AU - Sena-Esteves, Miguel
AU - Varela-Nallar, Lorena
AU - Rots, Marianne G.
AU - Montecino, Martin
AU - Van Zundert, Brigitte
N1 - Funding Information:
This work was supported by Fondecyt 1140301, ALS Therapy Alliance-2014-F-034, Anillo-RING ACT1114, and FONDEQUIP EQM 140166 (B.v.Z.); DRI USA 2013-0030 (B.v.Z., L.V.-N., M.M.); Nucleus DI-603-14/N and DI-4-17/N (B.v.Z., L.V.-N., J.S.); FONDAP 15090007 and Fondecyt 1170878 (M.M.); FP7-PEOPLE-2011-IRSES EULAMDIMA (B.v.Z., M.M.); Conicyt 24110099 (F.J.B.), Fondecyt-3130582 (E.A.); Conicyt 201161486 (N.J.); Fondecyt 1150933 (L.V.-N.); Fondecyt 3110138 (B.H.); FONDECYT 1130614, Anillo ACT-1414 and Millennium Nucleus NUMIND (NC-130011) Millenium Scientific Initiative of the Ministry of Economy, Development and Tourism (Chile) (M.F.); Fondecyt 1151029, FONDEQUIP EQM140119, CONICYT PIA ACT1402, ICM P09-015-F, CORFO 16CTTS-66390 and DAAD 57220037 & 57168868 CONICYT-PFB 12/2007 (J.T., S.H.). Basal Center of Excellence in Aging and Regeneration (N.C.I.). NIH/NINDS grant NS093941 (M.S-E).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - The Dlg4 gene encodes for post-synaptic density protein 95 (PSD95), a major synaptic protein that clusters glutamate receptors and is critical for plasticity. PSD95 levels are diminished in ageing and neurodegenerative disorders, including Alzheimer's disease and Huntington's disease. The epigenetic mechanisms that (dys)regulate transcription of Dlg4/PSD95, or other plasticity genes, are largely unknown, limiting the development of targeted epigenome therapy. We analysed the Dlg4/PSD95 epigenetic landscape in hippocampal tissue and designed a Dlg4/PSD95 gene-targeting strategy: a Dlg4/PSD95 zinc finger DNA-binding domain was engineered and fused to effector domains to either repress (G9a, Suvdel76, SKD) or activate (VP64) transcription, generating artificial transcription factors or epigenetic editors (methylating H3K9). These epi-editors altered critical histone marks and subsequently Dlg4/PSD95 expression, which, importantly, impacted several hippocampal neuron plasticity processes. Intriguingly, transduction of the artificial transcription factor PSD95-VP64 rescued memory deficits in aged and Alzheimer's disease mice. Conclusively, this work validates PSD95 as a key player in memory and establishes epigenetic editing as a potential therapy to treat human neurological disorders.
AB - The Dlg4 gene encodes for post-synaptic density protein 95 (PSD95), a major synaptic protein that clusters glutamate receptors and is critical for plasticity. PSD95 levels are diminished in ageing and neurodegenerative disorders, including Alzheimer's disease and Huntington's disease. The epigenetic mechanisms that (dys)regulate transcription of Dlg4/PSD95, or other plasticity genes, are largely unknown, limiting the development of targeted epigenome therapy. We analysed the Dlg4/PSD95 epigenetic landscape in hippocampal tissue and designed a Dlg4/PSD95 gene-targeting strategy: a Dlg4/PSD95 zinc finger DNA-binding domain was engineered and fused to effector domains to either repress (G9a, Suvdel76, SKD) or activate (VP64) transcription, generating artificial transcription factors or epigenetic editors (methylating H3K9). These epi-editors altered critical histone marks and subsequently Dlg4/PSD95 expression, which, importantly, impacted several hippocampal neuron plasticity processes. Intriguingly, transduction of the artificial transcription factor PSD95-VP64 rescued memory deficits in aged and Alzheimer's disease mice. Conclusively, this work validates PSD95 as a key player in memory and establishes epigenetic editing as a potential therapy to treat human neurological disorders.
KW - Alzheimer's disease
KW - ATF
KW - epigenetics
KW - PSD-95
KW - ZFP
UR - http://www.scopus.com/inward/record.url?scp=85038232228&partnerID=8YFLogxK
U2 - 10.1093/brain/awx272
DO - 10.1093/brain/awx272
M3 - Article
C2 - 29155979
AN - SCOPUS:85038232228
SN - 0006-8950
VL - 140
SP - 3252
EP - 3268
JO - Brain
JF - Brain
IS - 12
ER -
