SEMINAR

Full-length TDP-43 Forms Toxic Amyloid Oligomers in Frontotemporal Lobar Dementia-TDP Patients and Disturbs Amyloid-β Fibrillization

Abstract
TDP-43 proteinopathy consist of several neurodegenerative diseases including frontotemporal lobar dementia (FTLD), amyotrophic lateral sclerosis (ALS), and Alzheimre’s disease (AD). It is characterized by inclusion bodies formed by polyubiquitinated and hyperphosphorylated full-length and truncated TDP-43. The structural properties of TDP-43 aggregates and their relationship to the pathogenesis are still ambiguous. Here, we first demonstrated that the recombinant full-length human TDP-43 forms structurally stable, spherical oligomers with a diameter around 50 nm that share common epitopes with amyloid oligomers. The TDP-43 oligomers are stable, have exposed hydrophobic surfaces, exhibit reduced DNA binding capability, and are neurotoxic in vitro and in vivo. Moreover, TDP-43 oligomers are capable of cross-seeding Alzheimer’s amyloid-β to form amyloid oligomers, showing the inter-convertability between the amyloid species. Using a conformational antibody against TDP-43 oligomers, we demonstrated such oligomers are present in the forebrain of transgenic TDP-43 mice and hippocampus and cortex of FTLD-TDP patients. We further studied the effect and interaction of TDP-43 to Aβ fibrillization. We found TDP-43 oligomers affect Aβ at the early stage but not at the fibril stage. Aβ oligomers generated in the presence of TDP-43 are cytotoxic. Our results suggest that TDP-43 oligomers aside from filamentous aggregates reside in TDP-43 pathogenesis and TDP-43 oligomers may also play an important role in Alzheimer’s disease.

References
(1) Yu-Sheng Fang, Kuen-Jer Tsai, Yu-Jen Chang, Patricia Kao, Rima Woods, Pan-Hsien Kuo, Cheng-Chun Wu, Jhih-Ying Liao, Shih-Chieh Chou, Vinson Lin, Lee-Way Jin, Hanna S. Yuan, Irene H Cheng, Pang-Hsien Tu, and Yun-Ru Chen*. “Full-Length TDP-43 Forms Toxic Amyloid Oligomers that are Present in Frontotemporal Lobar Dementia-TDP Patients.” (2014) Nature Communications, 5:4824, 1-13.

(2) Patricia F. Kao, Yun-Ru Chen, Xiao-Bo Liu, Charles DeCarli, William W. Seeley, and Lee-Way Jin*. Detection of TDP-43 oligomers in frontotemporal lobar degeneration-TDP. (2015)Annals of Neurology, 24431.

BIOGRAPHY

2014-present: Associate Research Fellow, Genomics Research Center, Academia Sinica, Taiwan
2015-present: Adjunct Professor, Dept. of Biochemical Science & Technology, National Taiwan University, Taiwan
2015-2019: The World Academy of Sciences (TWAS) Young Affiliate
2014-2017: Council Member of Asia Pacific Protein Association (APPA)
2007-2014: Assistant Research Fellow, Genomics Research Center, Academia Sinica, Taiwan
2006-2007: Postdoctoral Fellow, Genomics Research Center, Academia Sinica, Taiwan
2004-2006: Postdoctoral Fellow, Dept. of Molecular Biology & Biochemistry, University of California, Irvine, USA
2003: PhD, Department of Molecular and Structural Biochemistry, North Carolina State University, USA

Research Fields and Interests:
Our long-term goal is to elucidate the disease mechanisms of amyloidosis in the aspects of protein folding and structure, pathogenic protein interactions, and relate the results to the medical consequences. Currently, we are working on several amyloids and amyloid-like proteins and their interacting partners in neurodegenerative diseases. They are amyloid-β (Aβ) peptide and tau protein, the major substance in senile plaques and neurofibrillary tangles of Alzheimer’s Disease (AD) patients respectively, α-synuclein, the component of Lewy bodies in Parkinson Disease, and TDP-43, a novel inclusion found in a subtype of frontotemporal lobar dementia (FTLD-U), amyotrophic lateral sclerosis (ALS), and AD. The major research interests are (1) Protein folding and misfolding of amyloids in neurodegenerative diseases; (2) Amyloid protein oligomerization and the toxicity mechanisms in neurodegenerative diseases; (3) Interactions of proteins, glycans, and lipids with the proteins involved in pathogenesis of the neurodegenerative diseases; (4) Drug screening, diagnostic, and therapeutic developments in neurodegenerative diseases

Selected Publications:
1. Yu-Sheng Fang, Kuen-Jer Tsai, Yu-Jen Chang, Patricia Kao, Rima Woods, Pan-Hsien Kuo, Cheng-Chun Wu, Jhih-Ying Liao, Shih-Chieh Chou, Vinson Lin, Lee-Way Jin, Hanna S. Yuan, Irene H Cheng, Pang-Hsien Tu, and Yun-Ru Chen*. “Full-Length TDP-43 Forms Toxic Amyloid Oligomers that are Present in Frontotemporal Lobar Dementia-TDP Patients.” (2014) Nature Communications, 5:4824, 1-13.

2. Yu-Jen Chang and Yun-Ru Chen*. The Co-existence of an Equal Amount of Alzheimer’s Amyloid-β 40 and 42 forms Structurally Stable and Toxic Oligomers through a Distinct Pathway. (2014) FEBS Journal, 281, 2674-2687.

3. Man Hoang Viet, Chun-Yu Chen, Chin-Kun Hu, Yun-Ru Chen*, and Mai Suan Li*. Discovery of Dihydrochalcone as a potential lead for Alzheimer’s disease: in silico and in vitro study. (2013) PLoS One, 8(11):e79151.

4. Yi-Hung Liao, Yu-Jen Chang, Yuji Yoshiike, Yu-Chorng Chang*, and Yun-Ru Chen*. Negatively charged gold nanoparticles inhibit Alzheimer’s amyloid- fibrillization, induce fibril dissociation, and mitigate neurotoxicity. (2012) Small, 8, 23, 3631-3639.

5. Chun-Lun Ni, Hoi-Ping Shi, Hui-Ming Yu, Yun-Chorng Chang, and Yun-Ru Chen*. Folding Stability of Amyloid-40 Monomer is an Important Determinant of the Nucleation Kinetics in Fibrillization. (2011) FASEB J., 25(4), 1390-401.

6. Wei-Ting Chen, Yi-Hung Liao, Hui-Ming Yu, Irene Cheng, and Yun-Ru Chen*. Distinct Effects of Zn2+, Cu2+, Fe3+, and Al3+ on Amyloid- Stability, Oligomerization, and Aggregation: Amyloid- Destabilization Promotes Annular Protofibril Formation. (2011) J Biol. Chem., 286 (11), 9646-56.