ntubst2019EN

Protein Folding/Misfolding, Amyloids, and Neurodegenerative Diseases

My research focuses on understanding the mechanism of protein misfolding diseases, amyloidosis, by various techniques including biochemical, biophysical, molecular, and cellular methods. 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. We further utilize the knowledge to develop novel diagnostic means and therapeutic modalities. Many ageing-related neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) belong to amyloidosis. Among them, AD is the most serious problem in the 21st century. Amyloidosis is caused by aggregation of misfolded proteins to form amyloid fibrils comprising specific cross-β structures. Amyloid oligomers that exist in several neurodegenerative diseases imply a common toxicity mechanism in different neurodegenerative diseases. Currently, we are working on three amyloid 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 AD patients respectively, α-synuclein, the component of Lewy bodies in PD, and TDP-43, a novel inclusion found in a subtype of frontotemporal lobar dementia (FTLD-U), amyotrophic lateral sclerosis (ALS), and AD. We start from elucidating the mechanism of such aggregation and further developing the diagnostic method, antibodies, and small molecule inhibitors. Moreover, we study the structure, function, and interactions of the related glycan conjugates, precursor proteins, and modifiers. The major research interests are listed as follows:

• Protein folding and misfolding of amyloids in neurodegenerative diseases.
• Amyloid protein oligomerization and the toxicity mechanisms in neurodegenerative diseases.
• Interactions of proteins, glycans, and lipids with the proteins involved in pathogenesis of the neurodegenerative diseases.
• Drug screening, diagnostic, and therapeutic developments in neurodegenerative diseases.

Amyloid formation, a detrimental protein aggregation, is initiated by protein 
misfolding followed by self-association to ultimately form amyloid fibrils.
The discovery of cytotoxic pre-fibrillar oligomers in many neurodegenerative 
diseases underscores the importance of understanding the folding, aggregation,
and pathogenic mechanisms as well as developing diagnostic and therapeutic
methods.

1. Ya-Ling Chiang, Yu-Jen Chang, Yun-Ru Chen*, and Ing-Shouh Hwang*, 2020, “Effects of Dissolved Gases on Amyloid Fibril Morphology”, LANGMUIR, 37(1), 516-523. (SCIE)
2. Yao-Hsiang Shih§, Ling-Hsien Tu§, Ting-Yu Chang, Kiruthika Ganesan, Wei-Wei Chang, Pao-Sheng Chang, Yu-Sheng Fang, Yeh-Tung Lin, Lee-Way Jin, and Yun-Ru Chen*, 2020, “TDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer’s disease”, NATURE COMMUNICATIONS, 11, 5950. (SCIE)
3. Phillip Smethurst, Emmanuel Risse, Giulia E. Tyzack, Jamie S. Mitchell, Doaa M. Taha, Yun-Ru Chen, Jia Newcombe, John Collinge, Katie Sidle and Rickie Patani*, 2020, “Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis”, BRAIN, 143(2), 430-440. (SCIE)
4. Shih-Ling Huang, Lien-Szu Wu, Min Lee, Chin-Wen Chang, Wei-Cheng Cheng, Yu-Sheng Fang, Yun-Ru Chen, Pei-Lin Cheng, Che-Kun James Shen*, 2020, “A Robust TDP-43 Knock-In Mouse Model of ALS”, Acta Neuropathologica Communications, 8(1),3. (SCIE)
5. Ling-Hsien Tu, Ning-Hsuan Tseng, Ya-Ru Tsai, Tien-Wei Lin, Yi-Wei Lo, Jien-Lin Charng, Hua-Ting Hsu, Yu-Sheng Chen, Rong-Jie Chen, Ying-Da Wu, Yi-Tsu Chan, Chang-Shi Chen, Jim-Min Fang,* and Yun-Ru Chen*, 2018, “Rationally Designed Divalent Caffeic Amide Inhibits Amyloid-β Fibrillization, Induce Fibril Dissociation, and Ameliorate Cytotoxicity”, EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 158, 393-404. (SCIE)
6. Chia-Jung Kuo, Hsu-Cheng Chiang, Chi-Ang Tseng, Chin-Fu Chang, Rajesh Kumar Ulaganathan, Tzu-Ting Ling, Yu-Jen Chang, Chiao-Chen Chen, Yun-Ru Chen, and Yit-Tsong Chen*., 2018, “A Lipid-Modified Graphene-Transistor Biosensor for Monitoring Amyloid-β Aggregation”, ACS APPLIED MATERIALS & INTERFACES, 10(15), 12311-12316. (SCIE)
7. Ming-Che Lee, Wan-Cheng Yu, Yao-Hsiang Shih, Chun-Yu Chen, Zhong-Hong Guo, Shing-Jong Huang, Jerry C. C. Chan, and Yun-Ru Chen*, 2018, “Zinc ion rapidly induces toxic, off-pathway amyloid-β oligomers distinct from amyloid-β derived diffusible ligands in Alzheimer’s disease”, Scientific Reports, 8, 4772. (SCIE)
8. Lin TW, Chang CF, Chang YJ, Liao YH, Yu HM, Chen YR*., 2017, “Alzheimer's amyloid-β A2T variant and its N-terminal peptides inhibit amyloid-β fibrillization and rescue the induced cytotoxicity”, PLOS ONE, 12(3), e0174561. (SCIE)
9. Smethurst, Phillip*; Newcombe, Jia; Troakes, Claire;Simone, Roberto; Wadsworth, John; Hardy, John; Chen, Yun-Ru; Patani, Rickie; Sidle, Katie, 2016, “ In vitro prion-like mechanisms of TDP-43 in ALS”, NEUROBIOLOGY OF DISEASE, 96, 236-247. (SCIE)
10. Nguyen Quoc Thai, Ning-Hsuan Tseng, Mui Thi Vu, Tin Trung Nguyen, Huynh Quang Linh, Chin-Kun Hu*, Yun-Ru Chen*, and Mai Suan Li*, 2016, “Discovery of DNA dyes Hoechst 34580 and 33342 as good candidates for Alzheimer’s disease: in silico and in vitro study”, JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 30(8), 639-50. (SCIE)
11. Yu-Jen Chang, Nguyen Hoang Linh, Hui-Ming Yu, Mai Suan Li*, and Yun-Ru Chen*, 2016, “Alzheimer’s Amyloid-β Sequesters Caspase-3 in vitro via its C-terminal Tail.”, ACS Chemical Neuroscience, 7(8), 1097-1106. (SCIE)
12. Yu-Jen Chang, U-Ser Jeng, Ya-Ling Chiang, Ing-Shouh Hwang, and Yun-Ru Chen*, 2016, “Glycine-Alanine Dipeptide Repeat from C9orf72 Hexanucleotide Expansions Forms Toxic Amyloids Possessing Cell-to-cell Transmission Property”, Journal of Biological Chemistry, 291(10), 4903-4911. (SCIE)
13. Chia‑Wei Lee, Lan‑Ling Jang, Huei‑Jyuan Pan, Yun‑Ru Chen, Chih‑Cheng Chen, and Chau‑Hwang Lee*, 2016, “Membrane roughness as a sensitive parameter reflecting the status of neuronal cells in response to chemical and nanoparticle treatments”, Journal of Nanobiotechnology, 14, 9. (SCIE)
14. Yi-Hung Liao and Yun-Ru Chen*, 2015, “A novel method for expression and purification of authentic amyloid-β with and without 15N labels.”, PROTEIN EXPRESSION AND PURIFICATION, 113, 63-71. (SCIE)
15. Patricia F. Kao, Yun-Ru Chen, Xiao-Bo Liu, Charles DeCarli, William W. Seeley, and Lee-Way Jin*, 2015, “Detection of TDP-43 oligomers in frontotemporal lobar degeneration-TDP”, ANNALS OF NEUROLOGY, 78(2), 211-221. (SCIE)
16. 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*, 2014, “Full-Length TDP-43 Forms Toxic Amyloid Oligomers that are Present in Frontotemporal Lobar Dementia-TDP Patients.”, Nature Communications, 5, 4824. (SCIE)
17. Yu-Jen Chang, Yun-Ru Chen*, 2014, “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”, FEBS JOURNAL, 281(11), 2674-2687. (SCIE)
18. Huei-Jyuan Pan, Ruei-Lin Wang, Jian-Long Xiao, Yu-Jen Chang, Ji-Yen Cheng, Yun-Ru Chen, and Chau-Hwang Lee, 2014, “Using optical profilometry to characterize cell membrane roughness influenced by Amyloid-beta 42 aggregates and electric fields”, Journal of Biomedical Optics, 19(1), 011009. (SCIE)
19. Man Hoang Viet, Chun-Yu Chen, Chin-Kun Hu, Yun-Ru Chen*, and Mai Suan Li*., 2013, “Discovery of Dihydrochalcone as potential lead for Alzheimer's disease: in silico and in vitro study”, PLoS One, 8(11), e79151. (SCIE)
20. Rong-Jie Chen, Wei-Wei Chang, Yu-Chun Lin, Pei-Lin Pheng, Yun-Ru Chen*, 2013, “Alzheimer’s Amyloid-β Oligomers Rescue Cellular Prion Protein Induced Tau Reduction via Fyn Pathways”, ACS Chemical Neuroscience, 4(9), 1287-1296. (SCIE)
21. 3. Wei-Chieh Cheng*, Chen-Yi Weng, Wen-Yi Yun, Shang-Yu Chang, Yu-Chun Lin, Fuu-Jen Tsai, Fu-Yung Huang, Yun-Ru Chen., 2013, “Rapid modifications of N-substitution in iminosugars: Development of new β-glucocerebrosidase inhibitors and pharmacological chaperones for Gaucher disease. ”, BIOORGANIC & MEDICINAL CHEMISTRY, 1, 5021-5028. (SCIE)
22. Yi-Ting Wang, Pan-Hsien Kuo, Chien-Hao Chiang, Jhe-Ruei Liang, Yun-Ru Chen, Shuying Wang, James C. K. Shen, and Hanna S. Yuan*., 2013, “The truncated C-terminal RRM domain of TDP-43 plays a key role in forming proteinaceous aggregates.”, J Biol. Chem., 288(13), 9049-9057. (SCIE)
23. Winny Ariesandi, Chi-Fon Chang, Tseng-Erh Chen,Yun-Ru Chen*, 2013, “Temperature-dependent structural changes of Parkinson's alpha-synuclein reveal the role of pre-existing oligomers in alpha-synuclein fibrillization”, PLoS One, 8(1), e53487. (SCIE)
24. Yi-Hung Liao, Yu-Jen Chang, Yuji Yoshiike, Yun-Chorng Chang*, and Yun-Ru Chen*, 2012, “Negatively charged gold nanoparticles inhibit Alzheimer's amyloid-beta fibrillization, induce fibril dissociation, and mitigate neurotoxicity”, SMALL, 8(23), 3631-3639. (SCIE)
25. Wei-Ting Chen, Chen-Jee Hong, Ya-Tzu Lin, Wen-Han Chang, He-Ting Huang, Jhih-Ying Liao, Chih-Ya Cheng, Hsiu-Chih Liu, Yun-Ru Chen*, and Irene H Cheng *, 2012, “Amyloid-beta (Abeta) D7H mutation increases oligomeric Abeta42 and alters properties of Abeta-zinc/copper assemblies ”, PLos One, 7(4), e35807. (SCIE)
26. Chun-Lun Ni, Hoi-Ping Shi, Kuo-Ging Lin, Hui-Ming Yu, and Yun-Ru Chen*, 2011, “Folding Stability of Amyloid-beta 40 Monomer is an Important Determinant of the Nucleation Phase in Fibrillization”, Faseb Journal, 25(4),1390-1401. (SCIE)
27. Wei-Ting Chen, Yi-Hung Liao, Hui-Ming Yu, Irene H. Cheng, and Yun-Ru Chen*, 2011, “Distinct Effects of Zn2+, Cu2+, Fe3+, and Al3+ on Amyloid-beta Stability, Oligomerization, and Aggregation: Amyloid-beta Destabilization Promotes Annular Protofibril Formation”, Journal of Biological Chemistry, 286(11), 9646-9656. (SCIE)
28. Ni-Shian Lin, John Ching-Hao Chao, Fang-Chieh Chou, Chi-Fon Chang, Yun-Ru Chen, Yu-Jen Chang, Shing-Jong Huang, Wei-Hsiang Tseng, and Jerry C. C. Chan, 2010, “Molecular Structure of Amyloid Fibrils Formed by Residues 127 to 147 of the Human Prion Protein”, Chemistry - A European Journal, 16(18), 5492-5499. (SCIE)
29. Yuji Yoshiike, Ryoichi Minai, Yo Matsuo, Yun-Ru Chen, Tetsuya Kimura, Akihiko Takashima* , 2008, “Amyloid Oligomer Conformation in a Group of Natively Folded Proteins”, PLos ONE., 3(9), e3235. (SCIE)
30. Yun-Ru Chen and Charles G. Glabe*, 2006, “Distinct Early Folding and Aggregation Properties of Alzheimer Amyloid-b Peptide Aβ40 and Aβ42: Stable Trimer or Tetramer Formation by Ab42”, J Biol. Chem, 281, 24414-24422. (SCIE)
31. Yun-Ru Chen and A. Clay Clark*, 2006, “Substitutions of prolines examine their role in kinetic trap formation of the caspase recruitment domain (CARD) of RICK”, Protein Science, 15, 395-409. (SCIE)
32. Yun-Ru Chen and A. Clay Clark*, 2004, “Kinetic traps in the folding/unfolding of procaspase-1 CARD Domain”, Protein Science, 13, 2196-2206. (SCIE)
33. Yun-Ru Chen and A. Clay Clark*, 2003, “Equilibrium and Kinetic Folding of the α-Helical Greek Key Protein Domain: Caspase Recruitment Domain (CARD) of RICK”, Biochemistry, 42, 6310-6320. (SCIE)
34. C. Pop, Y. R. Chen, B. Smith, K. Bose, B. Bobay, A. Tripathy, S. Franzen and A. C. Clark*, 2001, “Removal of the pro-domain does not affect the conformation of the procaspase-3 dimer”, Biochemistry, 40, 14224-14235. (SCIE)