Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer’s disease mice

Abstract

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.

Large-scale proteomic analysis of human prefrontal cortex identifies proteins associated with cognitive trajectory in advanced age

“…Here we show that the aggregate of PSD-95 interactome abundance is also associated with cognitive trajectory. Bustos and colleagues showed that increased protein level of PSD95 in the hippocampus rescued memory deficits of aged mice and dementia mice 53 . Their finding is consistent with ours in which over-expression of PSD95 protein was associated with cognitive stability.…”

PDZ Domains as Drug Targets

“…[102] PSD-95 encoding gene (DLG4) is found on chromosome 17 (17p13.1), spanning approximately 30 kb, and is associated with neurological disorders as previously discussed. [105] PSD-95 has also been found to have higher expression levels in the lateral amygdala in patients with MDD, compared to healthy individuals, [106] while a recent study showed no difference in epigenetic factors in the prefrontal cortex and hippocampus. Variations in DLG4 have been associated with schizophrenia [103,104] and it was recently shown that epigenetic editing of DLG4 could rescue memory deficits in a mouse model of Alzheimer's disease.…”

Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice

“…We assessed the long-term (24 h) spatial memory in 6-month-old C9BAC and control mice, using the object location memory (OLM) task. OLM is a simple single-trial behavioral memory task, in which rodents are allowed to explore freely (avoiding stress) and rely on the rodent's innate preference for novelty [49,50]. Animals were presented with a non-displaced (ND) versus displaced (D) object in the OLM test (Fig.…”