α-Synucleinopathies is characterized with accumulation of misfolded α-synuclein (α-syn), including Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). Braak’s prion-like theory fundamentally subverts the understanding of PD and related α-synucleinopathies. Emerging evidence shows that pathologic α-syn is a prion-like protein that spreads from one region to another in PD brain, which is an essential driver to the pathogenesis of PD.
In the cell-to-cell transmission of pathogenic α-syn, we identified that lymphocyte-activation gene 3 (LAG3) is an essential receptor that mediates the internalization of α-syn preformed fibrils (PFF) (Science 2016)1. Deletion and inhibition of LAG3 significantly impede α-syn pathology spread. We have provided the mechanistic understanding on the spread of pathological proteins and provides structural information for the therapeutic targeting of pathological α-syn spread (PNAS 2021)2 . Not only for α-synucleinopathy, Lag3 is also the receptor of pathogenic tau, and depletion of neuronal Lag3 can significantly inhibit pathogenic tau propagation and related dementia (Adv Sci 2024)3. SARS-CoV-2 infection (COVID-19) could lead to pathogenic tau propagation (JMV 2024)4. We further determined that LAG3 antibody (i.p.) can significantly inhibit both α-synucleinopathy and tauopathy. Pathogenic α-syn can cause neurodegeneration via PARP1 activation. Depletion and inhibition of PARP1 can significantly inhibit α-syn induced neurotoxicity and PAR-PFF strain spreading (Science 2018)5.
Because pathogenic α-syn seeds can drive the disease progression, it is important to target the intracellular α-syn aggregates. However, traditional antibodies fail to penetrate into plasma membrane, which cannot efficiently inhibit the propagation of α-synuclein. We developed a nanobody library and screened several nanobodies that bind to α-syn fibrils. By AAV-transduction, the nanobody can significantly inhibit the pathogenic α-syn spreading (Nature Comm 2022)6. These studies provide the new insights of therapeutic development of α-syn-related pathogenesis. (4) Pathogenic α-syn and ROS (reactive oxidative species) can form a feed-forward loop driving disease. Inhibition of the ROS can significantly inhibit cell-to-cell transmission of pathogenic α-syn (Nano Today 2021)7.
