Prof. Joseph Jen-Tse Huang
Title: From Protein Phase Transitions to Therapeutics: Understanding and Targeting Protein Misfolding in Neurodegenerative Disease
Abstract:
The aberrant phase transition and misfolding of intrinsically disordered proteins into neurotoxic aggregates is a shared hallmark of amyotrophic lateral sclerosis (ALS) and Huntington’s disease. Understanding how these transitions occur, and reversing them, remains a central challenge for disease-modifying therapies. This seminar presents our chemical-biology strategy spanning peptide design, optical control of protein phase behavior, and targeted protein degradation.
Synthetic peptide fragments of the TDP-43 C-terminal domain reveal that a glycine-rich region nucleates amyloid fibril formation, and that pathological mutations reshape aggregation propensity while preserving an amyloid architecture. To gain spatiotemporal control, we engineered photocontrollable peptide probes. A light-triggered probe from an amyloidogenic TDP-43 sequence self-assembles into vesicles that, upon photoactivation, seed endogenous TDP-43 into neurotoxic fibrils in live cells, impair nucleocytoplasmic trafficking, and recapitulate ALS pathogenesis on demand. A complementary droplet-forming peptide, JSF1, acts as a phase modulator that enhances condensation of fused in sarcoma (FUS) protein and drives its fibrillization under light, offering a direct way to probe the link between phase transition and proteinopathy in cells.
To challenge the view that misfolded proteins are undruggable, we then designed proteolysis-targeting chimeras (PROTACs). A TDP-43-directed PROTAC selectively degrades both aggregates and toxic oligomers without affecting endogenous protein, relieves cytotoxicity, and restores motility in transgenic C. elegans. Extending this strategy, a brain-penetrant PROTAC against mutant huntingtin spares wild-type protein and, in a mouse model of Huntington’s disease, improves body weight, motor coordination, and survival with reduced neuroinflammation. Together, our studies illustrate how chemical-biology tools can connect the study of protein phase transitions with the development of aggregate-selective strategies for neurodegenerative proteinopathies.
Selected References:
1. PROTAC-Mediated Degradation of mHTT Aggregates Attenuates Neurotoxicity in Cellular and R6/2 Mouse Models of Huntington’s Disease. J. Am. Chem. Soc. 2026, 148, 8, 8107–8121
2. Engineered Droplet-Forming Peptide as Photocontrollable Phase Modulator for Fused in Sarcoma Protein. Nat. Commun. 2024, 15, 5686
3. Degradation of Neurodegenerative Disease-associated TDP-43 Aggregates and Oligomers via a Proteolysis-Targeting Chimera. J. Biomed. Sci. 2023, 30, 27.
4. Photo-Controllable Probe Spatiotemporally Induces Neurotoxic Fibrillar Aggregates and Impairs Nucleocytoplasmic Trafficking. ACS Nano 2017, 11(7), 6795–6807.
5. Induction of Amyloid Fibrils by the C-Terminal Fragments of TDP-43 in Amyotrophic Lateral Sclerosis. J. Am. Chem. Soc. 2010, 132, 1186-1187
Bio:
Joseph Jen-Tse Huang is a Research Fellow (Professor) at the Institute of Chemistry, Academia Sinica, in Taipei, Taiwan. He received his Ph.D. from National Taiwan University and carried out postdoctoral research at Academia Sinica and the University of Wisconsin-Madison. His laboratory works at the interface of chemical biology, biophysics, and nanomedicine, developing molecular tools to understand and target protein misfolding in neurodegenerative diseases such as ALS and Huntington’s disease. One current focus is the design of engineered droplet-forming peptides that modulate the phase behavior of biomolecular condensates, including TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS), to reveal how liquid-to-solid transitions drive proteinopathy. The lab also develops photocontrollable peptide probes for the spatiotemporal control of protein aggregation, along with PROTAC-based approaches that degrade pathological TDP-43 and mutant huntingtin aggregates. His work has been recognized with the Academia Sinica Career Development Award, the Taiwan Motor Neuron Disease Association Research Award, and the Ministry of Science and Technology Excellent Young Scholar Award, among others.