In the past 10 years, my lab has made four major breakthroughs in unravelling the disease mechanisms underlying neurodegenerative and neurological diseases at Tsinghua University, School of Medicine, where I attained tenure as a Full Professor in 2022. Over the next 5 years, we will continue our journey on disease mechanism characterization and translate our research into clinical application, as described below:
1) CLCC1 is an ER anion channel that has little sequence similarity with any known ion channels. We are committed to unravelling its channel architecture/structure by cryo-electron microscopy. Given that CLCC1 is the first well-defined pore-forming component of intracellular organelle anion channels (Cell Res. 2023, PMID: 37142673), its gating mechanism is crucial for elucidating the roles and functions of intracellular anion channels. Lighting on whether the disruption of CLCC1 impairs memory formation by affecting internal Ca2+ release in learning and memory development is also of importance to us. Moreover, we aim to investigate whether neuronal [Cl-]ER, which is regulated by CLCC1, undergoes changes in these processes.
2) For the spliceosome pausing – a term originally coined by our group (Protein Cell. 2023, PMID: 37027487) – at the dtained introns (DI), our research delineates the upstream molecular signaling pathways that regulate DI splicing. We are dedicated to characterizing the type of introns that are prone to become DIs and addressing whether overrepresented DIs are pathogenic.
3) The dysfunction of RNA-binding proteins (RBPs) contributes to ALS pathogenesis, and many ALS mutant RBPs are stress granule (SG) components. Therefore, we aim to explore the dysregulation of SG assembly and disassembly in ALS and to understand how ALS mutant RBPs contribute to this dysregulation. By generating ALS mutant RBP knock-in (KI) animal models, which more accurately reflect the disease pathology compared to conventional transgenic overexpression approaches, we demonstrated for the first time that pathogenic SG assembly in vivo and SG misprocessing are pathogenic in mammals (Brain. 2020, PMID: 32358598). In addition, we observed that the same ALS mutation can lead to distinct disease progression in different animal species. By comparing the RNA/protein profiles of ALS models with varying disease progression, we identified a gene encoding a secreted protein that is upregulated 10 times in the KI mouse but not in the KI Bama pig ALS model. Loss-of-function of this secreted protein induces oxidative stress and accelerates the KI mouse ALS-like phenotypes. Soon, we are determined to translate our ALS research into clinical application.
4) TCF7L2 was first found by our team, using mouse-forward genetics, to be involved in mammal vocalization (Mol Psychiatry. 2023, PMID: 36782064). We are committed to identifying the downstream genes regulated by TCF7L2 that mediate their role in mammal vocalization. Given that autism-associated TCF7L2 mutant mice display severe ultrasonic vocalization impairment, we are interested in uncovering the role of TCF7L2 in the evolution of human language. The Tsinghua University Nonhuman Primate Research Center (THU-NPRC) was established in 2021 with a focus on the common marmoset, a highly vocal and social New World primate species. Marmosets are nonhuman primates that can be genetically manipulated, and their relatively high reproduction rates make them extremely attractive animal models for diseases. Therefore, we plan to generate marmoset carrying TCF7L2 autism-associated mutation by base-editing approach and study their vocalization complexity together with their social abilities. Moreover, we are excited to express wildtype TCF7L2 using an AAV-mediated gene delivery approach in mutant marmoset brains. This approach shows great promise in rescuing the mutant phenotypes and developing therapeutics for autism patients carrying the TCF7L2 mutations.