We use Drosophila and iPSC-derived neurons as models to study the pathomechanism of neurodegenerative diseases. Particularly, our research focuses on the role of mitochondria, nucleocytoplasmic transport, stress granules, and phase separation in ALS and FTD pathogenesis. We also use human multiomic analyses to identify novel therapeutic targets for these diseases.

During Dr. Zhang’s Ph.D research, he and others identified an important pathogenic pathway by which mitochondrial oxidative stress disrupts lipid metabolism in several neurodegenerative diseases, and a drug targeting this pathway suppresses neurodegeneration. In his postdoctoral laboratory, he and others identified nucleocytoplasmic transport defects as a critical pathogenic event in amyotrophic lateral sclerosis (ALS, a.k.a. Lou Gehrig’s disease) and frontotemporal dementia (FTD) caused by mutations in C9ORF72, the most common genetic cause of ALS/FTD (Zhang et al., Nature, 2015). This discovery was considered as a major breakthrough in the field. In addition, he has also identified a mechanistic connection between disrupted nucleocytoplasmic transport and stress granule assembly, a crucial player in ALS/FTD pathogenesis (Zhang et al., Cell, 2018). Recently, his research group identified a critical role of poly(ADP-ribose) in phase separation and aggregation of proteins implicated in C9ORF72-mediated ALS/FTD (Gao et al., Science Translational Medicine, 2022). 

Xiong Y, Ma C, Li Q, Zhang W, Zhao H, Ren P, Zhang K*, Lei X*. (2023) Melatonin ameliorates simulated-microgravity-induced mitochondrial dysfunction and lipid metabolism dysregulation in hepatocytes. FASEB Journal. 37(9):e23132.

Sahana TG#, Chase K, Liu F, Rossoll W, Lloyd TE, and Zhang K*. (2023) c-Jun N-terminal Kinase Promotes Stress Granule Assembly and Neurodegeneration in C9orf72-mediated ALS and FTD. Journal of Neuroscience. 43(17):3186-3197. 

Gao J, Mewborne QT, Girdhar A, Sheth U, Coyne AN, Punathil R, Kang BG, Dasovich M, Veire A, Liu S, Shi Z, Dafinca R, Fouquerel E, Talbot K, Kam T-I, Zhang Y-J, Dickson D, Petrucelli L, Guo L, Dawson TM, Dawson VL, Leung AKL, Lloyd TE, Gendron TF, Rothstein JD, and Zhang K*. Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins. Science Translational Medicine. 2022, In print

Maxwell B, Gwon Y, Mishra A, Peng J, Nakamura H, Zhang K, Kim HJ and Taylor JP. Ubiquitination is essential for recovery of cellular activities following heat shock. Science. 2021;372(6549):eabc3593; DOI: 10.1126/science.abc3593

Tang X, Toro A, T G Sahana, Gao J, Chalk J, Oskarsson B, Zhang K*. Divergence, Convergence, and Therapeutic Implications: A Cell Biology Perspective of C9ORF72-ALS/FTD. Review. Molecular Neurodegeneration. 2020;15(1):34.

Zhang K, Daigle JG, Cunningham KM, Coyne AC, Ruan K, Grima JC, Bowen KE, Wadhwa H, Yang P, Rigo F, Taylor JP, Gitler AD, Rothstein JD, Lloyd TE. Stress granule assembly disrupts nucleocytoplasmic transport, Cell. 2018;173(4):958-971.e17.

Zhang K*, Rothstein JD*. Neurodegenerative disease: Two-for-one on potential therapies. Preview. Nature. 2017;544(7650):302-303. 

Zhang K, Donnelly CJ*, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 525(7567):56-61.

Zhang K, Li Z, Jaiswal M, Bayat V, Xiong B, Sandoval H, Charng WL, David G, Haueter C, Yamamoto S, Graham BH, Bellen HJ. (2013) The C8ORF38 homologue Sicily is a cytosolic chaperone for a mitochondrial complex I subunit. J Cell Biol. 200(6):807-20.