Research Summary
The nervous system has extremely complex RNA processing regulation. Dysfunction of RNA metabolism has emerged to play crucial roles in multiple neurological diseases. Mutations and pathologies of several RNA-binding proteins, such as TDP-43, FUS/TLS, hnRNP A1 and A2B1, are found to be associated with neurodegeneration in ALS and FTD. An alternative RNA-mediated toxicity arises from micro-satellite repeat instability in the human genome. For example, hexanucleotide repeat expansion in C9orf72 is the most prevalent genetic cause of both ALS and FTD. The expanded repeat-containing RNAs could potentially induce neuron toxicity by disrupting protein and RNA homeostasis through various mechanisms.
The Sun lab is interested in deciphering the RNA processing pathways altered by the ALS-causative mutants to uncover the mechanisms of toxicity and molecular basis of cell type-selective vulnerability. Another major focus of the group is to identify small molecule and genetic inhibitors of neuron toxic factors using various high-throughput screening platforms. Her lab is also highly interested in developing novel CRISPR technique-based therapeutic strategies. The Sun lab seeks to translate the mechanistic findings at molecular level to therapeutic target development to advance treatment options against neurodegenerative diseases.
Lab
Lab Website: The Sun Laboratory
Selected Publications
View all on PubMed
Cheng W, Wang S, Mestre AA, Fu C, Makarem A, Xian F, Hayes LR, Lopez-Gonzalez R, Drenner K, Jiang J, Cleveland DW, Sun S. (2018) C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation. Nat Commun. 9(1): 51
Cheng W, Wang S, Zhang Z, Morgens DW, Hayes LR, Lee S, Portz B, Xie Y, Nguyen BV, Haney MS, Yan S, Dong D, Coyne A, Yang J, Xian F, Cleveland DW, Qiu Z, Rothstein JD, Shorter J, Gao F-B, Bassik MC, Sun S. (2019) CRISPR-Cas9 screens identify the RNA helicase DDX3X as a repressor of C9ORF72 (GGGGCC)n repeat-associated non-AUG translation. Neuron 104:1-14
Wang S, Latallo MJ, Zhang Z, Huang B, Bobrovnikov DG, Dong D, Livingston NM, Tjoeng W, Hayes LR, Rothstein JD, Ostrow LW, Wu B*, Sun S**. (2021) Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD. *Nature Communications 12:4908
Li Y, Dou X, Liu J, Xiao Y, Zhang Z, Wu R, Fu X, Ye Y, Hayes L, Ostrow L, He C, ****Sun S. (2023) Globally reduced N6-methyladenosine (m6A) in C9ORF72-ALS/FTD dysregulates RNA metabolism and contributes to neurodegeneration. Nature Neuroscience. 26(8):1328-1338
Latallo MJ, Wang S, Dong D, Nelson B, Livingston NM, Wu R, Zhao N, Stasevich TJ, Bassik MC, Sun S, Wu B. (2023) Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD. Nature Communications 14: 5581. *co-corresponding auithors
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