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Modulation of histone deacetylase 2 (HDAC2) drives neuronal gene expression, mitochondrial dynamics and AD pathophysiology in human stem cell derived neurons
Author(s) -
Frankowski Harald,
Berry Bonnie J.,
Yeboah Fred,
Evitts Kira,
Kinoshita Chizuru,
Kinoshita Yoshito,
Morrison Richard S.,
Young Jessica E.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.037263
Subject(s) - histone deacetylase 2 , biology , induced pluripotent stem cell , microbiology and biotechnology , phenotype , histone deacetylase , gene expression , histone , gene , genetics , embryonic stem cell
Background Histone deacetylase 2 (HDAC2) is a major HDAC protein in the adult brain and has been shown to regulate many neuronal genes. Aberrant expression of HDAC2 and subsequent dysregulation of neuronal gene expression has been implicated in Alzheimer’s disease (AD) and brain aging. In vitro models of AD and other neurodegenerative disorders using human induced pluripotent stem cells (hiPSCs) are being increasingly utilized and have provided novel insights into disease mechanisms. However, the role of HDAC2 in living, human neurons and how its manipulation in an AD model may affect disease phenotypes has not been investigated. Method We used human induced pluripotent stem cells and lentiviral‐mediated manipulation of HDAC2 in hiPSC‐derived neurons to study the effects of increasing or decreasing HDAC2 expression on neuronal mitochondrial gene expression, morphology, and AD phenotypes. Result In this study, we show that levels of HDAC2 naturally decrease as hiPSCs are differentiated towards a neuronal lineage and that this suppression of HDAC2 inversely corresponds to an increase in neuronal‐specific isoforms of Endophilin‐B1, a multifunctional protein involved in mitochondrial dynamics. Manipulation of HDAC2 and Endophilin‐B1 using lentiviral approaches shows that knock‐down of HDAC2 or overexpression of Endophilin‐B1 promote mitochondrial elongation in hiPSC‐derived neurons, but HDAC2 knock‐down specifically influences genes regulating neuronal mitochondrial dynamics. We also observe that the endogenous decrease in HDAC2 levels upon neuronal differentiation also correlates with natural increases in neuronal activity and knock‐down of HDAC2 in differentiated neurons increases expression of genes related to neuronal synapses and further increases neuronal firing. Finally, we demonstrate that knock‐down of HDAC2 reduces amyloid beta peptides and the phospho/total Tau ratio in iPSC‐derived neurons. Conclusion Collectively, our study demonstrates that HDAC2 regulates key neuronal functional and bioenergetic pathways in hiPSC‐derived neurons and suggests that HDAC2 may represent a novel therapeutic target for AD.