School of Public Health
We are interested in the biological basis for protein and RNA homeostasis in neurodegeneration. We hope to solve problems that not only have biological significance but also have important implications for understanding and treating disease.
Discovering key regulators of protein homeostasis: Protein misfolding plays a central role in the pathogenesis of many neurodegenerative diseases, including Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Elucidating the mechanisms that connect the misfolded proteins to neurodegeneration is a critical step to understand these diseases and to develop novel and effective therapies. We use unbiased genetic screens to understand how cells boost protein quality control to counter the effects of the misfolded proteins. We are also investigating hidden protein quality control regulatory pathways, building on an emerging paradigm in which post-translational modification switches act on previously unrecognized networks that reprogram the protein quality control systems. In addition, we study the regulation of protein synthesis under stress conditions, which is implicated in a myriad of human diseases.
Uncovering novel players in the regulation of RNA homeostasis: Because perturbation of RNA homeostasis in the central nervous system is another major theme in neurodegeneration, we are interested in studying new pathways of RNA processing. We have uncovered novel functions of RNA-binding proteins linked to neurodegeneration, showing impacts on protein quality control regulation, gene silencing activity mediated by mature miRNAs, and in phase transition and stress granule formation.
Revealing the mechanisms of repeat expansion diseases: We are interested in understanding the biology of a hexanucleotide repeat expansion in the C9orf72 gene that is the most common cause of ALS and FTD, and may serve as a model for understanding other neurodegenerative diseases with similar repeat expansions. Our studies have pointed to a molecular cascade that connects the structure of the C9orf72 nucleotide repeat to cellular defects and human pathology. Our investigations will uniquely bridge the study of repeat structures and molecular pathology, providing further proof of concept for targeting toxic conformations of nucleic acids as a treatment intervention. We are also investigating the role of the C9orf72 protein in the regulation of autophagy and metabolism, which have critical roles in the functioning of the nervous system.
Liu Y, Huang Z, Liu H, Ji Z, Arora A, Cai D, Wang H, Liu M, Simko E, Zhang Y, Periz G, Liu Z, Wang J. DNA-initiated Epigenetic Cascades Driven by C9orf72 Hexanucleotide Repeat. Neuron 111(8):1205-1221.e9.
Wang T, Tian X, Jang Y, Huang Z, Na CH, Wang J. (2022) Intracellular Energy Controls Dynamics of Stress-induced Ribonucleoprotein Granules. Nature Communications 13(1):5584.
Tang Q, Liu M, Liu Y, Hwang R, Zhang T, Wang J. (2021) NDST3 deacetylates α‐tubulin and suppresses V‐ATPase assembly and lysosomal acidification. EMBO J. 40 (19):e107204.
Liu H, Lu YN, Pau T, Periz G, Banco MT, Ferre-D’Amare AR, Rothstein JD, Hayes LR, Myong S, Wang J. A Helicase Unwinds Hexnucleotide Repeat RNA G-Quadruplexes and Facilitates Repeat-Associated Non-AUG Translation. J. Am. Chem. Soc. 143(19):7368-7379.
Lu YN*, Kavianpour S*, Zhang T, Zhang X, Nguyen D, Thombre R, He L, Wang J. (2021) MARK2 Phosphorylates eIF2α in Response to Proteotoxic Stress. PLoS Biology 19(3):e3001096.
Wang T, Liu H, Itoh K, Oh S, Zhao L, Murata D, Sesaki H, Hartung T, Na CH, Wang J. (2021) C9orf72 Regulates Energy Homeostasis by Stabilizing Mitochondrial Complex I Assembly. Cell Metabolism 33(3):531-546.e9.
Zhang T*, Periz G*, Lu Y, Wang J. (2020) USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L-SMAD pathway. PNAS 117(45):28114-28125.
Simko E, Liu H, Zhang T, Velasquez A, Teli S, Haeusler AR, Wang J. (2020) G-quadruplexes offer a conserved structural motif for NONO recruitment to NEAT1 architectural IncRNA. Nucleic Acids Res. 48:7421-7438.
Ji Y, Ugolino J, Zhang T, Lu J, Kim D, Wang J. (2020) C9orf72/ALFA-1 Controls TFEB/HLH-30-dependent Metabolism Through Dynamic Regulation of Rag GTPases. PLoS Genetics 16(4):e1008738.
Lu J*, Periz G*, Lu Y*, Tang Q, Liu Y, Zhang T, Shah Y, Thombre R, Aljumaah R, Li W, Mojsilovic-Petrovic J, Ji Y, Johnson K, Kalb R, Wang J. (2019) L3MBTL1 Regulates ALS/FTD-associated Proteotoxicity and Quality Control. Nature Neuroscience 22(6):875-886.
Alexander E, Niaki A, Zhang T, Sarkar J, Liu Y, Nirujogi R, Pandey A, Myong S, Wang J. (2018) Ubiquilin 2 Modulates ALS/FTD-linked FUS-RNA Complex Dynamics and Stress Granule Formation. Proc. Natl. Acad. Sci. USA 115(49):E11485-E11494.
Liu Y, Wang T, Ji Y, Johnson K, Liu H, Johnson K, Bailey S, Suk Y, Lu Y, Liu M, Wang J. (2018) A C9orf72-CARM1 Axis Regulates Lipid Metabolism Under Glucose Starvation-induced Nutrient Stress. Genes & Development 32:1380-1397.
Zhang T, Wu Y, Mullane P, Ji Y, Liu H, He L, Arora A, Hwang H, Alessi A, Miaki A, Periz G, Guo L, Wang H, Elkayam E, Joshua-Tor L, Myong S, Kim J, Shorter J, Ong S, Leung A, Wang J. (2018) FUS Regulates Activity of MicroRNA-mediated Gene Silencing. Molecular Cell 69:787-801.
Hwang H, Wang J. (2017) Effects of mutation mechanisms on variant composition and distribution in Caenorhabditis elegans. PLoS Comput Biol. 13(1):e1005369.
Ugolino J*, Ji Y*, Conchina K, Chu J, Nirujogi RS, Pandey A, Brady N, Hamacher-Brady A, Wang J. (2016) Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling. PLoS Genet 12(11): e1006443.
Periz G, Lu J, Kankle M, Jablonski A, Kalb R, McCampbell A, Wang J. (2015) Regulation of protein quality control by UBE4B and LSD1 through p53-mediated transcription. PLoS Biology 13(4):e1002114.
Zhang T, Baldie G, Periz G, Wang J. (2014) RNA-processing protein TDP-43 regulates FOXO-dependent protein quality control in stress response. PLoS Genetics, 10(10):e1004693.
Haeusler AR, Donnelly C, Periz G, Simko E, Shaw P, Kim M, Maragakis N, Troncoso J, Pandey A, Sattler R, Rothstein J, and Wang J. (2014) C9orf72 Nucleotide Repeat Structures Initiate Molecular Cascade of Disease. Nature 507:195-200.
Zhang T. Hwang H.Y., Hao H., Talbot C., Jr., and Wang J. (2012) Caenorhabditis elegans RNA-processing Protein TDP-1 Regulates Protein Homeostasis and Lifespan. J Biol Chem. 287, 8371-8382.
Zhang T, Mullane PC, Periz G, Wang J. (2011) TDP-43 Neurotoxicity and Protein Aggregation Modulated by Heat Shock Factor and Insulin/IGF-1 Signaling. Hum Mol Genet, 20, 1952-1965.