RNA metabolism dysfunction and RNA-targeting therapy in neurodegeneration
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 are found to be associated with neurodegeneration in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s Disease (AD). An alternative RNA-mediated toxicity arises from microsatellite repeat instability in the human genome. 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 genetic modifiers of neuronal toxicity using CRISPR screening platforms. We seek to translate the mechanistic findings at molecular level to therapeutic target and biomarker development to advance treatment options against neurodegenerative diseases.
Li Y, Dou X, Liu J, Xiao Y, Zhang Z, Wu R, Fu X, Ye Y, Hayes L, Ostrow L, *He C, *Globally reduced N6-methyladenosine (m6A) in C9ORF72-ALS/FTD dysregulates RNA metabolism and contributes to neurodegeneration. Nature Neuroscience. doi: 10.1038/s41593-023-01374-9.. (2023)
Wang S and Translation dysregulation in neurodegenerative diseases: a focus on ALS. Molecular Neurodegeneration 18:58.. (2023)
Latallo MJ, Wang S, Dong D, Nelson B, Livingston NM, Wu R, Zhao N, Stasevich TJ, Bassik MC, Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD. Nature Communications 14: 5581., Wu B*. (2023)
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.
Zaepfel BL, Zhang Z, Maulding K, Coyne AN, Cheng W, Lloyd TE*, Sun S*, Rothstein JD*. (2021) UPF1 reduces C9orf72 HRE-induced neurotoxicity in the absence of nonsense-mediated decay dysfunction. Cell Reports 34(13): 108925.
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 AN, 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.
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. Nature Communications 9:51.
Sun S, Sun Y, Ling SC, Ferraiuolo L, McAlonis-Downes M, Zou Y, Drenner K, Wang Y, Ditsworth D, Tokunaga S, Kopelevich A, Kaspar BK, Lagier-Tourenne C, and Cleveland DW. (2015) Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS. Proc Natl Acad Sci U S A. 112(50): E6993-7002.
Sun S, Ling SC, Qiu J, Albuquerque CP, Zhou Y, Tokunaga S, Li H, Qiu H, Bui A, Yeo GW, Huang EJ, Eggan K, Zhou H, Fu XD, Lagier-Tourenne C, Cleveland DW. (2015) ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nature Communications 6: 6171.