Neurons rely on intracellular transport to deliver newly synthesized organelles and macromolecules to the far-reaching ends of their neurites and to carry cargos such as neurotrophic factors back to the soma to alter gene expression. Defects in long-range intracellular transport have emerged as a common factor of several neurodegenerative disorders. Neurons, on the other hand, are large, long-lived post-mitotic cells that cannot rely on cellular division to dilute accumulated misfolded proteins and damaged organelles. Therefore, it is critical for neurons to maintain intracellular protein homeostasis and remove abnormal organelles. We are interested in understanding macromolecular machinery's structural basis and molecular mechanisms related to neurological diseases. Using a combination of biochemical, electrophysiology, crystallography, and electron microscopic experiments we have obtained insights into various biological processes. Ultimately, we intend to obtain a “molecular movie” of more processes at high resolution so that they can be understood at a detailed mechanistic level. With the interdisciplinary nature of the approaches applied in my lab, findings from the proposed study will not only bring deep mechanistic understandings into intracellular transport and organelle homeostasis but also pave the way for developing novel diagnostic and therapeutic means targeting neurological disorders-related pathways.
Our recent focus is to understand how intracellular transport and mitochondrial functions contribute to neuronal health maintenance, including:
1) Molecular mechanism of the organelle interaction and how it contributes to maintaining homeostasis.
2) The structural basis of the coordination of neuronal transport and local translation, and the mechanisms by which defects lead to neurological diseases.
3) Mechanistic insight into organelle membrane protein quality control.
Shen X, Sun P, Zhang H*, Yang H*. (2022) Mitochondrial quality control in the brain: The physiological and pathological roles. Front. Neurosci. 16:1075141.
Yang HT#, *, Desai N# (2021). Purification of mitochondrial ribosomes with the translocase Oxa1L from HEK cells. Bio-protocol, 11(15): e4110.
Desai N#, Yang HT#, Chandrasekaran V#, Kazi R, Minczuk M, Ramakrishnan V* (2020). Elongational Stalling Activates Mitoribosome-associated Quality Control. Science, 6520 (370): 1105-1110. DOI: 10.1126/science.abc7782
Yang HT#, Hu MH#, Guo JL, Ou XM, Cai TX, Liu ZF* (2016). Pore architecture of TRIC channels and insights into their gating mechanism. Nature, 7626 (538): 537-541.
Zhang C*, Yang HT, Liu ZF, Sun F (2018). Thermodynamics of voltage-gated ion channels. Biophysics Reports, 4(6): 300-319.
Chandrasekaran V#, Desai N#, Burton N#, Yang HT, Price J, Miska E*, Ramakrishnan V* (2021). Visualising formation of the ribosomal active site in mitochondria. eLife 10:e68806.
Ou XM#, Guo JL#, Wang LF, Yang HT, Liu XY, Sun JY, Liu ZF*. (2017) Ion and water binding sites inside an occluded hourglass pore of a TRIC channel. BMC Biology, 15(1): 31.
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