Dr. Wang received his Ph.D. in pathology from the Case Western Reserve University in 2009. Following postdoctoral training at the Department of Pathology, he was promoted to Instructor of Pathology in 2011 and has became an Assistant Professor in 2013.
Alzheimer’s disease (AD) is the most prevalent form of dementia characterized by neuronal loss in the neocortex and hippocampus. Frontotemporal dementia (FTD) is the second most common form of early-onset dementia caused by neuronal loss in the frontal and temporal cortex. Amyotrophic lateral sclerosis (ALS) is the most common motor disease characterized by progressive motor neuron degeneration in brain stem and spinal cord. My research interest is to understand the mechanism(s) underlying neuronal death in various major neurodegenerative diseases with a focus on AD, FTD and ALS.
Pathomechanisms of TDP-43 neurotoxicity
Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause ALS and FTD, and the increased presence of TDP-43 in the cytoplasm is a prominent histopathological feature of degenerating neurons in ALS, FTD and AD. One major focus of our current research is about the molecular pathomechanisms of TDP-43.
Mitochondrial dysfunction in FTD and ALS
Mitochondrial dysfunction has long been recognized as a prominent feature of FTD and ALS. However, the mechanisms responsible for the mitochondrial impairment, and its role in these diseases were not clear. Mitochondria are dynamic organelles that undergo continual fission and fusion events which serve crucial physiological function. Another focus of our research is the potential role of mitochondria dynamics in mitochondrial dysfunction and neurodegeneration in FTD and ALS.
Mitochondria in primary neurons (left) and neuronal cell lines (middle and right)
Gu, J., Chen, F., Iqbal, K., Gong, C.X., Wang, X. and Liu, F. (2017) Transactive response DNA-binding protein 43 (TDP-43) regulates alternative splicing of tau exon 10: implications for the pathogenesis of tauopathies. J Biol Chem. 292(25):10600-10612.
Gu, J., Wu, F., Xu, W., Shi, J., Hu, W., Jin, N., Qian, W., Wang, X., Iqbal, K., Gong, C.X. and Liu, F. (2017) TDP-43 suppresses tau expression via promoting its mRNA instability. Nucleic Acids Res. 45(10):6177-6193.
Wang, W., Arakawa, H., Wang, L., Okolo, O., Siedlak, S.L., Jiang, Y., Gao, J., Xie, F., Petersen, R.B. and Wang, X. (2017) Motor coordination and cognitive dysfunction caused by mutant TDP-43 could be reversed by inhibiting its mitochondrial localization. Mol Ther. 25(1):127-139. Comment on: “New Therapeutic Avenue for ALS: Avoiding a Fatal Encounter of TDP-43 at the Mitochondria” in Mol Ther. 2017, 25(1):10-11.
Wang, W., Wang, L., Lu, J., Siedlak, S.L., Fujiok, H., Liang, J., Jiang, S., Ma, X., Zhen, J., Rocha, E.L., Sheng, M., Choi, H., Lerou, P.H., Li, H., and Wang, X. (2016). The Inhibition of TDP-43 Mitochondrial Localization Blocks Its Neuronal Toxicity. Nat Med. 22(8):869-878. Comment on: “Unleashed From the Nucleus, TDP-43 Wreaks Havoc in Mitochondria” in ALZFORUM; “From the Bench: TDP-43 Accumulation in Mitochondria May Drive ALS/FTD Toxicity” in Neurology Today, 2016, 16(17), 42–44; “ALS Culprit Protein Chokes Mitochondria, Killing Neurons, According to Recent Discovery” in ALS NEWS TODAY; “Protein’s Misconduct in Mitochondria May Be Cause of Nerve Cell Death in Huntington’s” in the Huntington’s Disease News; “Scientists Prevent Nerve Cell Death and Neurodegenerative Disease Progression” in Kerafast; “Scientists keep a molecule from moving inside nerve cells to prevent cell death” by Case Western Reserve University School of Medicine.
Wang, W., Wang, X.*, Fujioka, H., Hoppel, C., Whone, A.L., Caldwell, M.A., Cullen, P.J., Liu, J.* and Zhu, X.* (2016). Parkinson's disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes. Nat Med. 22(1):54-63. *corresponding author.
Wang, C., Zhang, F., Jiang, S., Siedlak, S., Shen, L., Perry, G., Wang, X., Tang, B. and Zhu, X. (2016) Estrogen receptor-α is localized to neurofibrillary tangles in Alzheimer's disease. Sci. Rep. 6:20352.
Wang, W., Zhang, F., Li, L., Tang, F, Siedlak, S. L., Liu, Y., Su, B., Fujioka, H. and Wang, X. (2015) Mfn2 Couples Glutamate Excitotoxicity and Mitochondrial Dysfunction in Motor Neurons. J Biol Chem. 290:168-182. “Paper of the Week”
Zhang, F., Su, B., Wang, C., Siedlak, S.L., Mondragon-Rodriguez, S., Lee, Hyoung-gon., Wang, X., Perry, G. and Zhu, X. (2015) Posttranslational Modifictions of α-Tubulin in Alzheimer Disease. Transl. Neurodegener. 4: 9.
Zhang, F., Wang, W., Siedlak, S., Liu, Y., Liu, J., Jiang, K., Perry, G., Zhu, X., and Wang, X. (2015) Miro1 Deficiency in Amyotrophic Lateral Sclerosis. Front Aging Neurosci. 7:100.
Zhang, B., Cowden, D., Zhang, F., Yuan, J., Siedlak, S., Abouelsaad, M., Zeng, L., Zhou, X., O'Toole, J., Das, A.S., Kofskey, D., Warren, M., Bian, Z., Cui, Y., Tan, T., Kresak, A., Wyza, R.E., Petersen, R.B., Wang, G.X., Kong, Q., Wang, X., Sedor, J., Zhu, X., Zhu, H., Zou, W.Q. (2015) Prion Protein Protects against Renal Ischemia/Reperfusion Injury. PLoS One. 10(9):e0136923.
Blair, J.A., Palm, R., Chang, J., McGee, H., Zhu, X., Wang, X. and Casadesus, G. (2016) Luteinizing hormone downregulation but not estrogen replacement improves ovariectomy-associated cognition and spine density loss independently of treatment onset timing. Horm Behav. 2016 Feb;78:60-6. doi: 10.1016/j.yhbeh.2015.10.013. Epub 2015 Oct 21.