Invited Speaker 50th Lorne Proteins Conference 2025

Protein misfolding, pathogenic mechanism, and therapeutic potential for TDP-43 and dipeptide repeats in the neurodegenerative diseases (115949)

Yun-Ru Chen 1
  1. Academia Sinica, Taipei, Taiwan

Protein misfolding occurs in many neurodegenerative diseases without effective treatment. TDP-43 inclusions are found in the diseased lesions of ~95% of amyotrophic lateral sclerosis (ALS), ~50% of frontotemporal dementia (FTD), and nearly 57% Alzheimer’s disease (AD) patients. Those AD patients with TDP-43 pathology present faster disease progression and greater brain atrophy. The misfolding mechanism and pathogenesis of TDP-43 aggregation is still largely unknown. In 2014, we first discovered that recombinant full-length human TDP-43 forms toxic spherical oligomers and perturbs amyloid-β (Aβ) fibrillization(1). We compared the biochemical properties for TDP-43 oligomers and the hyperphosphorylated mimics(2), and further investigated the role of misfolded TDP-43 oligomers in AD(3). We demonstrated that TDP-43 inhibits Aβ fibrillization through its Aβ interaction and exacerbates AD pathology. TDP-43 oligomer-specific antibody, TDP-O, was generated to identify the misfolded species in AD/FTD/ALS patients. After intravenous (i.v.) administrated the antibody to ALS mouse models, the results showed significant rescue effects including increase of motor neuron survival, increase of reinnervation in neuromuscular junction, improvement of the motor behaviors, reduction of TDP-43 oligomers, and reduction of inflammation.

Next, I will present our recent study on investigation of toxicity and structural mechanism of dipeptide repeats (DPRs) translated from hexanucleotide repeat expansion in C9ORF72 (C9) in FTD/ALS(4,5). Hexanucleotide repeat expansion in C9ORF72 (C9) is the most prevalent mutation in FTD/ALS. The patients carry over ~30 to hundreds or thousands of repeats translated to dipeptide repeats (DPRs). The structure-function relationship of DPRs is still unknown. We first examined the aggregation properties of different DPRs and later focused on the arginine-rich DPRs. We found the helical formation and minimal neurotoxic repeat number of poly-GR and the function of membrane penetration and DNA damages. A sulfated disaccharide was further identified to rescue poly-GR/PR-induced toxicity in neuroblastoma and C9-ALS-iPSC-derived motor neurons as well as the animal models. 

  1. 1. Fang, Y. S., Tsai, K. J., Chang, Y. J., Kao, P., Woods, R., Kuo, P. H., Wu, C. C., Liao, J. Y., Chou, S. C., Lin, V., Jin, L. W., Yuan, H. S., Cheng, I. H., Tu, P. H., and Chen, Y. R.* (2014) Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients. Nature communications 5, 4824
  2. 2. Chiang, W. C., Fang, Y. S., Lye, Y. S., Weng, T. Y., Ganesan, K., Huang, S. H., Chang, L. Y., Chou, S. C., and Chen, Y. R.* (2022) Hyperphosphorylation-Mimetic TDP-43 Drives Amyloid Formation and Possesses Neuronal Toxicity at the Oligomeric Stage. Acs Chem Neurosci 13, 2599-2612
  3. 3. Shih, Y. H., Tu, L. H., Chang, T. Y., Ganesan, K., Chang, W. W., Chang, P. S., Fang, Y. S., Lin, Y. T., Jin, L. W., and Chen, Y. R.* (2020) TDP-43 interacts with amyloid-beta, inhibits fibrillization, and worsens pathology in a model of Alzheimer's disease. Nat Commun 11, 5950
  4. 4. Chang, Y. J., Jeng, U. S., Chiang, Y. L., Hwang, I. S., and Chen, Y. R.* (2016) The Glycine-Alanine Dipeptide Repeat from C9orf72 Hexanucleotide Expansions Forms Toxic Amyloids Possessing Cell-to-Cell Transmission Properties. J Biol Chem 291, 4903-4911
  5. 5. Chang, Y. J., Lin, K. T., Shih, O., Yang, C. H., Chuang, C. Y., Fang, M. H., Lai, W. B., Lee, Y. C., Kuo, H. C., Hung, S. C., Yao, C. K., Jeng, U. S., and Chen, Y. R.* (2024) Sulfated disaccharide protects membrane and DNA damages from arginine-rich dipeptide repeats in ALS. Sci Adv 10, eadj0347