biostudies-literatureTobe BTDHHS | NIH | National Institute of Mental HealthNIDA NIH HHSNIMH NIH HHSE4462-E4471https://www.ebi.ac.uk/biostudies/studies/S-EPMC5465887biostudies-literatureUnknown114(22)The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active nonphosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithiuProceedings of the National Academy of Sciences of the United States of AmericaProbing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis.PMC5465887RC2MH090011K01 DA038654R21 MH093958R33MH087896R01 MH087823RC2 MH090011R33 MH087896R01 MH095088R01MH095088R21MH093958McCarthy MJGoshima YZhao WNWu DLogan RWBasa RCBPernia CDUdeshi NDOhshima TKonopaske GRouleau GASheridan SDTobe BTDLi JDuerr CNakamura HPrice JHNakamura FChen GSnyder EYBrill LMAkiskal HSWada MCarr SAHunsberger JMakihara HMertins PDorsett LGutierrez GJInoue YNye JSAlda MMikoshiba KChuang DMTeng YDMastrangelo LMcClung CAHaggarty SJLiu YCoyle JTCrain AMVenizelos NManji HHalpain SSidman RLLalonde JWinquist AMBrandel MCalabrese BSidor MYamashita NfalseProbing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis.The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active nonphosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithiu2017-01-01T00:00:00Z2017 May2026-05-05T02:57:49.644Z2025-06-01T03:33:37.723ZS-EPMC54658872850027210.1073/pnas.1700111114