Joseph Jen-Tse Huang
Institute of Chemistry, Academia Sinica, Taipei, Taiwan
TAR DNA-binding protein (TDP-43) was identified as the main sediments in the histopathological inclusion bodies of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) in 2006. However, the pathological mechanism underlying these disorders remains vague. Our group have synthesized numerous TDP-43 peptides and illustrated that these fragments could form fibrillar aggregates, sharing similar morphology with neuronal cytoplasmic inclusions in ALS patients in 2010. Recently, we have further synthesized glutamine/asparagine (Q/N)-rich and glycine (G)-rich polypeptides from the TDP-43 C-terminus and characterized their structural/amyloidogenic properties with various biophysical methods. We demonstrated that only the amyloidogenic peptides, no matter from Q/N- or G-rich polypeptides, can induce the nascent TDP-43 aggregation in the cell-free system. Through the microinjection of carboxy-tetramethylrhodamine-attached peptides and real-time imaging, we have also proven that these aforementioned peptides are able to seed the aggregation of the TDP-43 in cells and trigger apoptosis. Our results directly demonstrate that the amyloidogenic properties, rather than the Q/N content, of the TDP-43 polypeptides dominate their prion-like behaviors, which may shed light on the TDP-43 proteinopathy in ALS and FTLD.
References:
He, R.-Y., Huang, Y.-C., Chiang, C.-W., Tsai, Y.-J., Ye, T.-J., Gao, H.-D., Wu, C.-Y., Lee, Y.-M.*, and Huang, J. J.-T.* Chem. Commun. 2015, 51, 8652-8655.
Sun, C.-S., Wang, C. Y.-H., Chen, B.-W., He, R.-Y., Wang, C.-H., Chen, W., Chern, Y., Huang, J. J.-T.* PLoS ONE 2014, 9(8), e103644.
Huang C.-C., Bose J.-K., Majumder P., Lee K.-H., Huang, J. J.-T., Huang J. K., Shen J. C.-K.* J. Cell Sci. 2014, 127, 3024-3038.
Liu, G. C.-H., Chen, B. P.-W., Ye, N. T.-J., Wang, C.-H., Chen, W., Lee, H.-M., Chan, S. I., Huang, J. J.-T.* Chem. Commun. 2013, 49, 11212-11214.
Huang, Y.-C. Lin, K.-F, He, R.-Y., Tu, P.-H. Koubek, J., Hsu,Y.-C., Huang, J. J.-T.* PLoS One 2013, 8(5), e64002.
Chang, C.-K., Wu, T.-H., Wu, C.-Y., Chiang, M.-H., Toh, E.-K., Hsu, Y.-C., Lin, K.-F., Liao, Y.-H., Huang, T.-H.*, Huang, J. J.-T.* Biochem. Biophys. Res. Commun. 2012, 425, 219-224.
Huang, J. J.-T.; Larsen, R.-W.; Chan, S.-I.* Chem. Commun. 2012, 48, 487-497.
Chen, K.-H.; Lin, Y.-Y.; Xie, Z.-J.; Tu, P.-H.; Chen, P.-Y.; Liao, T.-Y.; Chen, W.; Wang, C.-H.; Huang, J. J.-T.* J. Am. Chem. Soc. 2010, 132, 1186-1187.
