Research Areas

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.

Highlights

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). 

Honors

• 2019  Frick Foundation for ALS research Award

• 2018  Target ALS Foundation，Springboard Fellowship

• 2016  Johns Hopkins School of Medicine, Helen B. Taussig Research Award

• 2014  ALS Association (USA), Milton Safenowitz Postdoctoral Fellowship

Selective Publications

1. 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

2. 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

3. 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.

4. 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.

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

6. 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. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015;525(7567):56-61.

Commented/reported in:

a. Fox and Tibbetts, Nature. 2015;525: 36–7

b. Underwood, Science. 2015 Aug 28;349: 911-2

c. Blitterswijk and Rademakers, Nature Reviews Neurology. 2015;11: 670–2

d. Munteanu and Lynch, Front Neurol. 2016;7: 51

7. Liu L, Zhang K, Sandoval H, Yamamoto S, Jaiswal M, Sanz E, Li Z, Hui J, Graham BH, Quintana A, Bellen HJ. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell. 2015;160(1-2):177-90. 

8. Yamamoto S, Jaiswal M, Charng WL, Gambin T, Karaca E, Mirzaa G, Wiszniewski W, Sandoval H, Haelterman NA, Xiong B, Zhang K, Bayat V, David G, Li T, Chen K, Gala U, Harel T, Pehlivan D, Penney S, Vissers LELM, de Ligt J, Jhangiani SN, Xie Y, Tsang SH, Parman Y, Sivaci M, Battaloglu E, Muzny D, Wan YW, Liu Z, Lin-Moore AT, Clark RD, Curry CJ, Link N, Schulze KL, Boerwinkle E, Dobyns WB, Allikmets R, Gibbs RA, Chen R, Lupski JR, Wangler MF, Bellen HJ. A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell. 2014;159(1):200-214. 

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

10. Yamamoto S, Charng WL, Rana NA, Kakuda S, Jaiswal M, Bayat V, Xiong B, Zhang K, Sandoval H, David G, Wang H, Haltiwanger RS, Bellen HJ. A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands. Science. 2012;338(6111):1229-32.