One of the major focuses in the neuroscience field is to understand the pathogenic mechanisms underlying neurological and neurodegenerative diseases, which afflict millions of people worldwide. However, no effective therapeutic interventions have been developed to date. This is partially attributed to our limited knowledge of the molecular mechanisms underlying these debilitating disorders. In the JiaLab at Tsinghua, we aim to investigate the pathogenic mechanisms of and advance therapeutic-target discovery for neurodegenerative and neurodevelopmental diseases.
Our main approaches to achieve these goals include animal models of disease using chemical-induced mutant mice, such as mutagen ENU (N-ethyl-N-nitrosourea)-induced mutants. These disease models recapitulate the vital pathological mechanisms
of neurodegenerative and neurodevelopmental phenotypes. Intriguingly, mice share over 90% gene similarity with humans. The identification of disease mutant genes in mice has significantly deepened our insights into the disease mechanisms. Furthermore, what we have discovered about disease-causing and/or disease-modifying genes will enhance our understanding of their physiological functions in the brain.
Our group employs ENU-induced mutagenesis and screens for new genes or modifiers involved in neurological or neurodegenerative phenotypes. Our current research focuses include:
(1) Investigating the disease mechanisms underlying neurodegenerative and neurodevelopmental disorders resulting from RNA metabolism abnormalities and the dysregulation of ER homeostasis.
(2) Exploring molecular mechanisms underlying mammal vocalization and their dysfunctions in neurodevelopmental disorders.
(3) Developing novel cell and animal models for neurological and neurodegenerative diseases.
1. Disruption of ER ion homeostasis maintained by an ER anion channel leads to ALS-like pathology. Liang Guo, Qionglei Mao, Ji He, Xiaoling Liu, Xuejiao Piao, Li Luo, Xiaoxu Hao, Bailong Xiao, Dongsheng Fan, Zhaobing Gao, and Yichang Jia. Cell Research. 2023 May 04. doi:10.1038/s41422-023-00798-z. PMID: 37142673.
2. A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration. Dawei Meng, Qian Zheng, Xue Zhang, Li Luo, and Yichang Jia. Protein & Cell. 2023 May 08;14(5):318-336. PMID: 37027487.
3. TCF7L2 acts as a molecular switch in midbrain to control mammal vocalization through its DNA binding domain but not transcription activation domain. Huihui Qi, Li Luo, Caijing Lu, Runze Chen, Xiaohui Zhang, and Yichang Jia. Molecular Psychiatry. 2023 Feb 13. doi: 10.1038/s41380-023-01993-5. PMID: 36782064.
4. Dual-gRNA approach with limited off-target effect corrects C9ORF72 repeat expansion in vivo. Xuejiao Piao, Dawei Meng, Xue Zhang, Qiang Song, Hailong Lv, and Yichang Jia. Sci Rep. 2022 Apr 5;12(1):5672. doi: 10.1038/s41598-022-07746-8. PMID: 35383205.
5. In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model. Zhang X, Wang F, Hu Y, Chen R, Meng D, Guo L, Lv H, Guan J, Jia Y. Brain. 2020 May 1. doi: 10.1093/brain/awaa076. PMID: 32358598.
6. An ENU-induced mutation in Twist1 transactivation domain causes hindlimb polydactyly with complete penetrance and dominant-negatively impairs E2A-dependent transcription. Chen RZ, Cheng X, Tan Y, Chang TC, Lv H, Jia Y. Sci Rep. 2020 Feb 12;10(1):2501. doi: 10.1038/s41598-020-59455-9. PMID: 32051525.
7. Loss of Clcc1 results in ER stress, misfolded protein accumulation, and neurodegeneration. Jia Y, Jucius TJ, Cook SA, Ackerman SL. J Neurosci. 2015 Feb 18;35(7):3001-9. doi: 10.1523/JNEUROSCI.3678-14.2015. PMID: 25698737.
8. Mutation of a U2 snRNA gene causes global disruption of alternative splicing and neurodegeneration. Jia Y, Mu JC, Ackerman SL. Cell. 2012 Jan 20;148(1-2):296-308. doi: 10.1016/j.cell.2011.11.057. PMID: 22265417.
9. TRPC channels promote cerebellar granule neuron survival. Jia Y, Zhou J, Tai Y, Wang Y. Nat Neurosci. 2007 May;10(5):559-67. PMID: 17396124.
10. Critical role of TRPC6 channels in the formation of excitatory synapses. Zhou J, Du W, Zhou K, Tai Y, Yao H, Jia Y, Ding Y, Wang Y. Nat Neurosci. 2008 Jul;11(7):741-3. doi: 10.1038/nn.2127. PMID:18516035.
11. Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor. Li Y, Jia YC, Cui K, Li N, Zheng ZY, Wang YZ, Yuan XB. Nature. 2005 Apr 14;434(7035):894-8. PMID: 15758952.
