Summary: Researchers at Rush University Medical Center report that two intranasal peptides reduced brain inflammation and halted the spread of alpha-synuclein in mouse models of Parkinson’s disease. Treated animals also showed measurable improvements in gait, balance, and other motor functions. If these findings translate to humans, the investigators say the approach could represent a significant advance in treating Parkinson’s and related Lewy body disorders.
Source: Rush University Medical Center
New peptide-based treatments developed at Rush University Medical Center slow disease processes linked to Parkinson’s in preclinical mouse models.
In a peer-reviewed study published in Nature Communications, researchers from Rush report that two laboratory-designed peptides reduce the propagation of alpha-synuclein, the protein that aggregates into Lewy bodies in the brains of people with Parkinson’s disease. Lewy bodies are a pathological hallmark not only of Parkinson’s but also of related conditions such as dementia with Lewy bodies and multiple system atrophy (MSA).
“At present, available therapies for Parkinson’s disease address symptoms but do not slow or stop disease progression,” says Kalipada Pahan, PhD, the Floyd A. Davis Professor of Neurology at Rush University Medical Center and a research career scientist at the Jesse Brown VA Medical Center, who led the study. “Targeting mechanisms that drive alpha-synuclein spread and neuroinflammation is a promising strategy for disease-modifying treatment.”
The two experimental peptides tested are named the TLR2-interacting domain of MyD88 (TIDM) and the NEMO-binding domain (NBD). Delivered intranasally, both peptides reduced microglial-driven inflammation in the brain and limited the cell-to-cell spread of alpha-synuclein in mice seeded with pathogenic alpha-synuclein fibrils. Beyond biochemical and histological benefits, treated animals exhibited improvements in motor coordination, gait stability, and balance—outcomes that align with the functional goals for Parkinson’s therapies.
Mechanistically, the study implicates the TLR2/MyD88/NF-κB signaling pathway in the propagation of alpha-synuclein pathology. The investigators found that preformed alpha-synuclein fibrils promoted an increased association between TLR2 and MyD88, triggering microglial activation and inflammatory signaling. Targeting that interaction with the TIDM peptide, and inhibiting downstream NF-κB signaling with the NBD peptide, reduced inflammation and alpha-synuclein spread in vitro and in vivo.
In A53T transgenic mice that had been seeded with alpha-synuclein fibrils, nasal administration of the wild-type TIDM peptide (wtTIDM) or the wild-type NBD peptide (wtNBD) decreased glial inflammation, lowered measures of alpha-synuclein propagation, and protected dopaminergic neurons—effects the authors attribute to inhibition of the NF-κB pathway. Genetic deletion of TLR2 produced similar protective outcomes, supporting the central role of the TLR2/MyD88/NF-κB axis in this model.
“If these preclinical results can be reproduced and shown to be safe and effective in patients, they would represent a remarkable advance toward disease-modifying therapies for Parkinson’s disease and other Lewy body disorders,” Pahan says. The researchers emphasize, however, that translation from animal models to human clinical benefit requires further study, including safety profiling, dosing optimization, and well-controlled clinical trials.
Funding: This research was supported by funding from the National Institutes of Health.
Other contributors to the published study include Debashis Dutta, PhD; Malabendu Jana, PhD; Moumita Majumder, PhD; Susanta Mondal, PhD; and Avik Roy, PhD, all affiliated with Rush University Medical Center.
About this Parkinson’s disease research news
Author: Charles Jolie
Source: Rush University Medical Center
Contact: Charles Jolie – Rush University Medical Center
Image: The image is in the public domain
Original Research: Open access. “Selective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo” by Debashis Dutta, Malabendu Jana, Moumita Majumder, Susanta Mondal, Avik Roy & Kalipada Pahan. Nature Communications
Abstract
Selective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo
Pathways that control the spreading of alpha-synuclein (α-syn) and related neuropathology in Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) remain incompletely understood. This study demonstrates that preformed α-syn fibrils (PFF) enhance the association between TLR2 and MyD88, leading to microglial activation and inflammatory signaling.
Selective inhibition of TLR2 using a peptide that mimics the TLR2-interaction domain of MyD88 (wtTIDM) reduced PFF-induced microglial inflammation in vitro. In PFF-seeded A53T transgenic mice, nasal administration of wtTIDM or a peptide that blocks NF-κB activation (wtNBD), as well as genetic deletion of TLR2, lowered glial inflammation, decreased α-syn spreading, and protected dopaminergic neurons through inhibition of NF-κB signaling.
In summary, the results support a model in which α-syn spreading depends on signaling through the TLR2/MyD88/NF-κB pathway and can be attenuated by intranasal delivery of wtTIDM and wtNBD peptides in preclinical models.