CoREST Complex-Selective Histone Deacetylase Inhibitors Show Prosynaptic Effects and an Improved Safety Profile To Enable Treatment of Synaptopathies

Synaptic dysfunction is a pathological feature in many neurodegenerative disorders, including Alzheimer’s disease, and synaptic loss correlates closely with cognitive decline. Histone deacetylases (HDACs) are involved in chromatin remodeling and gene expression and have been shown to regulate synaptogenesis and synaptic plasticity, thus providing an attractive drug discovery target for promoting synaptic growth and function. To date, HDAC inhibitor compounds with prosynaptic effects are plagued by known HDAC dose-limiting hematological toxicities, precluding their application to treating chronic neurologic conditions. We have identified a series of novel HDAC inhibitor compounds that selectively inhibit the HDAC–co-repressor of repressor element-1 silencing transcription factor (CoREST) complex while minimizing hematological side effects. HDAC1 and HDAC2 associate with multiple co-repressor complexes including CoREST, which regulates neuronal gene expression. We show that selectively targeting the CoREST co-repressor complex with the representative compound Rodin-A results in increased spine density and synaptic proteins, and improved long-term potentiation in a mouse model at doses that provide a substantial safety margin that would enable chronic treatment. The CoREST-selective HDAC inhibitor Rodin-A thus represents a promising therapeutic strategy in targeting synaptic pathology involved in neurologic disorders

X-ray Structure of Citrate Bound to Src SH2 Leads to a High-Affinity, Bone-Targeted Src SH2 Inhibitor

X-ray Structure of Citrate Bound to Src SH2 Leads to a High-Affinity, Bone-Targeted Src SH2 Inhibito

Additional file 8 of Validation and test–retest repeatability performance of parametric methods for [11C]UCB-J PET

Additional file 8. Scatterplot for BPND estimated using SRTM2 with corresponding NLR (1T2k_VB) DVR-1 estimates separately color-coded for each region

Additional file 7 of Validation and test–retest repeatability performance of parametric methods for [11C]UCB-J PET

Additional file 7. Scatterplots for BPND estimated using SRTM2 for test and retest scans, separately for (a) HCs and (b) AD patients with corresponding NLR (1T2k_VB) DVR-1 estimates and separately color-coded for each subject. AD: Alzheimer’s disease; HC: healthy control; LOI: line of identity

Additional file 6 of Validation and test–retest repeatability performance of parametric methods for [11C]UCB-J PET

Additional file 6. Scatterplots for BPND estimated using RPM for test and retest scans, separately for (a) HCs and (b) AD patients with corresponding NLR (1T2k_VB) DVR-1 estimates and separately color-coded for each subject. AD: Alzheimer’s disease; HC: healthy control; LOI: line of identity

Additional file 3 of Validation and test–retest repeatability performance of parametric methods for [11C]UCB-J PET

Additional file 3. Scatterplot for VT estimated using SA with corresponding NLR (1T2k_VB) VT estimates separately color-coded for each region

Additional file 16 of Validation and test–retest repeatability performance of parametric methods for [11C]UCB-J PET

Additional file 16. TRT (%) values estimated for specific brain regions (grey matter) are presented for SA VT and K1

Additional file 4 of Validation and test–retest repeatability performance of parametric methods for [11C]UCB-J PET

Additional file 4. Scatterplot for K1 estimated using SA with corresponding NLR (1T2k_VB) K1 estimates separately color-coded for each region

Additional file 10 of Validation and test–retest repeatability performance of parametric methods for [11C]UCB-J PET

Additional file 10. TRT repeatability voxel-wise image (average and SD) for AD patients separately for SA VT, RPM BPND and SRTM2 BPND

Additional file 13 of Validation and test–retest repeatability performance of parametric methods for [11C]UCB-J PET

Additional file 13. Coefficients of determination (r2) and slopes of parametric [11C]UCB-J VT, K1 and BPND against corresponding 1T2k_VB estimates separately for all subjects. All the Hammers ROIs were included for this analysis. Regional parametric values from both test and retest scans were pulled together for these comparisons