Synucleinopathies are neurodegenerative disorders characterized by the progressive accumulation of α-synuclein (α-syn) in neurons and glia and include Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this review, we consolidate our key findings and recent studies concerning the role of Toll-like receptor 2 (TLR2), a pattern recognition innate immune receptor, in the pathogenesis of synucleinopathies. First, we address the pathological interaction of α-syn with microglial TLR2 and its neurotoxic inflammatory effects. Then, we show that neuronal TLR2 activation not only induces abnormal α-syn accumulation by impairing autophagy, but also modulates α-syn transmission. Finally, we demonstrate that administration of a TLR2 functional inhibitor improves the neuropathology and behavioral deficits of a synucleinopathy mouse model. Altogether, we present TLR2 modulation as a promising immunotherapy for synucleinopathies.
Keywords: Immunotherapy; Neuroinflammation; Synucleinopathy; Toll-like receptor 2; α-synuclein.
Immunotherapy Targeting Toll-Like Receptor 2 Alleviates Neurodegeneration in Models of Synucleinopathy by Modulating α-Synuclein Transmission and NeuroinflammationC Kim et al. Mol Neurodegener 13 (1), 43. PMID 30092810.This study proposes TLR2 immunotherapy as a novel therapeutic strategy for synucleinopathies of the aging population.
Toll-like Receptor 4 Stimulation With Monophosphoryl Lipid A Ameliorates Motor Deficits and Nigral Neurodegeneration Triggered by Extraneuronal α-SynucleinopathyS Venezia et al. Mol Neurodegener 12 (1), 52. PMID 28676095.Our findings demonstrate beneficial effects of chronic MPLA treatment in transgenic PLP-α-syn mice. MPLA appears to be an attractive therapeutic candidate for disease mod …
Non-cell-autonomous Neurotoxicity of α-Synuclein Through Microglial Toll-like Receptor 2C Kim et al. Exp Neurobiol 25 (3), 113-9. PMID 27358579.Synucleinopathies are a collection of neurological diseases that are characterized by deposition of α-synuclein aggregates in neurons and glia. These diseases include Par …
Neurotoxic Conversion of Beta-Synuclein: A Novel Approach to Generate a Transgenic Mouse Model of Synucleinopathies?M Fujita et al. J Neurol 256 Suppl 3, 286-92. PMID 19711118. - ReviewMany groups have generated alpha-synuclein (alpha-syn) transgenic (tg) mice as a rodent model for human synucleinopathies, including Parkinson's disease and dementia with …
Distinct α-Synuclein Strains and Implications for Heterogeneity Among α-SynucleinopathiesC Peng et al. Neurobiol Dis 109 (Pt B), 209-218. PMID 28751258. - ReviewThe deposition of misfolded β-sheet enriched amyloid protein is a shared feature of many neurodegenerative diseases. Recent studies demonstrated the existence of conforma …