A new study co-led by Scintillon Institute’s Associate Professor, Dr. Rajesh Ambasudhan, and Adjunct Professor Dr. Stuart Lipton (also a practicing Neurologist at UC San Diego) shows that certain immunotherapy approaches for Parkinson’s disease (PD) may cause harmful neuroinflammation by activating microglia (brain’s immune cells) and that this adverse effect could offset therapeutic benefits elicited by the antibody treatment. The study appeared in the April 13, 2021 issue of the Proceedings of the National Academy of Science of the United States of America.
PD is the second most prevalent neurodegenerative disorder. There is currently no cure available for millions of PD patients world-wide. A key pathological feature of the disease is the formation/propagation of abnormal aggregates of the protein named α-synuclein across the brain. Although the exact role of these protein aggregates in disease pathogenesis remains to be fully understood, their potentially causing brain inflammation has been suggested as a major contributing factor.
To understand the role of neuroinflammation in PD in a human context, the team set out to develop a robust platform to generate human microglia from induced pluripotent stem cells (iPSCs). In a leap of improvement over the current state of the art, the microglia cells generated using the new method more faithfully mimicked their counterparts in human brain. The addition of α-synuclein aggregates to these human microglia elicited an inflammatory response as expected. Next, the team added antibodies that recognize α-synuclein to the mixture of human microglia and α-synuclein aggregates. These antibodies were expected to physically clear α-synuclein aggregates during the PD pathogenesis and thus hoped to be therapeutically beneficial. Surprisingly, the team found that although these antibodies by themselves are non-toxic their complexes with α-synuclein aggregates worsened the inflammation rather than improving the outcome. In another twist to the tale, only microglia from humans but not those from mice - a widely used in vivo model system for testing therapies - showed such an elevated inflammatory response. These findings were further verified in the brains of mice in which the human immune system was reconstituted.
“Our study points to the importance of using human cells while developing immunotherapies for neurodegenerative diseases and uncovers a potential side effect, which at least in part explains the limited success of antibody-based clinical trials thus far in this field”, says Dr. Ambasudhan, who is also the Chief Strategist of Allele Biotechnology in San Diego, and an Adjunct Associate Professor at the Scripps Research Institute in La Jolla. “Because the inflammatory pathways we observed are mediated by Toll-like receptor 2, the compounds targeting these receptors could be beneficial in mitigating these adverse effects in future immunotherapies aimed at clearing the aggregates”, Dr. Ambasudhan commented further.
The study was a large collaboration between the Scintillon team and multiple research institutions across the country. The other senior authors were Dr. Michael Karin, a Professor at the UC San Diego Medical School, and Dr. Nicholas Schork, a Professor at the Translational Genomics Institute in Phoenix, AZ. Dr. Dorit Trudler, a post-doctoral fellow, co-supervised by Drs. Lipton and Ambasudhan, was the lead author of the study.
1. Soluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia.
Dorit Trudler, Kristopher L. Nazor, Yvonne S. Eisele, Titas Grabauskas, Nima Dolatabadi, James Parker, Abdullah Sultan, Zhenyu Zhong, Marshall S. Goodwin, Yona Levites, Todd E. Golde, Jeffery W. Kelly, Michael R. Sierks, Nicholas J. Schork, Michael Karin, Rajesh Ambasudhan, and Stuart A. Lipton. PNAS 2021 Vol. 118 No. 15 e2025847118