Frankowski, H. | Search bioRxiv

bioRxiv2025

Kat5 cKO Biological Domain Signatures Align with Human Alzheimer Disease

BACKGROUNDAlzheimers disease (AD) is associated with amyloid plaques and can be caused by autosomal dominant mutations in APP or PSEN1/2, which form an enzyme substrate complex. Decreases in catalysis of AD mutant APP and PSEN1 supports the hypothesis that membrane delimitation of KAT5 could contribute to AD. METHODSWe compare the hippocampal transcriptome profiles of the Kat5 brain-specific knockout mouse to multiple AD datasets through alignment with the TREAT-AD AD biological domains. We examine KAT5 subcellular localization in human WT and AD neurons. RESULTSThe Kat5 KO mouse demonstrates downregulation of synaptic genes, metabolic pathways, and upregulation of DNA replication and repair, cell cycle and immune response genes. We see similar profiles in Kat5 and comparative AD datasets. KAT5 is restricted to the cytosol in human AD neurons. DISCUSSIONThis analysis supports the hypothesis that KAT5 nuclear signaling down stream of APP cleavage plays a pivotal role in neuronal homeostasis and immune regulation.

neuroscience↗

bioRxiv2021

Histone Deacetylase 2 (HDAC2) influences maturation and mitochondrial dynamics in human induced pluripotent stem cell derived neurons.

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 is implicated in neurodegeneration and brain aging. Human induced pluripotent stem cell-derived neurons (hiPSC-Ns) are widely used models for studying neurodegenerative disease mechanisms, but the role of HDAC2 in hiPSC-N differentiation and maturation has not been explored. In this study, we show that levels of HDAC2 progressively decrease as hiPSCs are differentiated towards neurons. This suppression of HDAC2 inversely corresponds to an increase in neuron-specific isoforms of Endophilin-B1, a multifunctional protein involved in mitochondrial dynamics. Expression of neuron-specific isoforms of Endophilin-B1 is accompanied by concomitant expression of a neuron-specific alternative splicing factor, SRRM4. Manipulation of HDAC2 and Endophilin-B1 using lentiviral approaches shows that knock-down of HDAC2 or overexpression of a neuron-specific Endophilin-B1 isoform promotes mitochondrial elongation and protects against cytotoxic stress in hiPSC-Ns, while HDAC2 knock-down specifically influences genes regulating mitochondrial dynamics and synaptogenesis. Furthermore, HDAC2 knock-down promotes enhanced mitochondrial respiration and reduces levels of neurotoxic amyloid beta peptides. Collectively, our study demonstrates a role for HDAC2 in hiPSC-neuronal differentiation, highlights neuron-specific isoforms of Endophilin-B1 as a marker of differentiating hiPSC-Ns, and demonstrates that HDAC2 regulates key neuronal and mitochondrial pathways in hiPSC-Ns.

neuroscience↗