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Human stem cell-based cell replacement therapy for Parkinson's disease: Enhancing the survival of postmitotic dopamine neuron grafts

Sat, 31 Jan 2026 15:00:00 GMT

Title: Human stem cell-based cell replacement therapy for Parkinson's disease: Enhancing the survival of postmitotic dopamine neuron grafts Author(s): Kim, Tae Wan Abstract:

Phosphorylation-mediated disassembly of C-terminal binding protein 2 tetramer impedes epigenetic silencing of pluripotency in mouse embryonic stem cells

Thu, 31 Oct 2024 15:00:00 GMT

Title: Phosphorylation-mediated disassembly of C-terminal binding protein 2 tetramer impedes epigenetic silencing of pluripotency in mouse embryonic stem cells Author(s): Lee, Han-Teo; Kim, Young Ah; Lee, Sangho; Jung, Ye-Eun; Kim, Hanbyeol; Kim, Tae Wan; Kwak, Sojung; Kim, Jaehyeon; Lee, Chul-Hwan; Cha, Sun-Shin; Choi, Jinmi; Cho, Eun-Jung; Youn, Hong-Duk Abstract: Cells need to overcome both intrinsic and extrinsic threats. Although pluripotency is associated with damage responses, how stem cells respond to DNA damage remains controversial. Here, we elucidate that DNA damage activates Chk2, leading to the phosphorylation of serine 164 on C-terminal binding protein 2 (Ctbp2). The phosphorylation of Ctbp2 induces the disruption of Ctbp2 tetramer, weakening interactions with zinc finger proteins, leading to the dissociation of phosphorylated Ctbp2 from chromatin. This transition to a monomeric state results in the separation of histone deacetylase 1 from Ctbp2, consequently slowing the rate of H3K27 deacetylation. In contrast to the nucleosome remodeling and deacetylase complex, phosphorylated Ctbp2 increased binding affinity to polycomb repressive complex (PRC)2, interacting through the N-terminal domain of Suz12. Through this domain, Ctbp2 competes with Jarid2, inhibiting the function of PRC2. Thus, the phosphorylation of Ctbp2 under stress conditions represents a precise mechanism aimed at preserving stemness traits by inhibiting permanent transcriptional shutdown. © The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.

TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons

Sun, 30 Jun 2024 15:00:00 GMT

Title: TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons Author(s): Kim, Tae Wan; Koo, So Yeon; Riessland, Markus; Chaudhry, Fayzan; Kolisnyk, Benjamin; Cho, Hyein S.; Russo, Marco Vincenzo; Saurat, Nathalie; Mehta, Sanjoy; Garippa, Ralph; Betel, Doron; Studer, Lorenz Abstract: Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, an unresolved challenge is the extensive cell death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival in vivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-α)-nuclear factor κB (NF-κB) signaling in limiting cell survival. As a translationally relevant strategy to purify postmitotic dopamine neurons, we identified cell surface markers that enable purification without the need for genetic reporters. Combining cell sorting and treatment with adalimumab, a clinically approved TNF-α inhibitor, enabled efficient engraftment of postmitotic dopamine neurons with extensive reinnervation and functional recovery in a preclinical PD mouse model. Thus, transient TNF-α inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic hPSC-derived dopamine neurons in PD. © 2024 The Authors