Objective: In this study we aimed to investigate the potential role of Toll-like receptor 4 (TLR4) in mediating both the dopaminergic neuron loss and alpha-synuclein (alpha-SYN) accumulation in a mouse model of Parkinson’s disease (PD). To do this we used WT and TLR4-deficient mice (TLR4-/-).
Background: TLRs predominantly contribute to immune-related disorders. However, new evidences suggest that neuronal TLR activation participates in the pathogenesis of neurodegenerative synucleinpathies, including PD. TLR4 dysregulation is thought to correlate with neurodegeneration and brain injury.
Method: WT and TLR4-/- mice were exposed to the acute1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) regimen. Mice (n=5 per group) received four i.p. injections at 2-h intervals. Seven days post-MPTP intoxication, mice were sacrificed by cervical dislocation and several brain regions were isolated. Immunohistochemistry, western immunoblotting, and real time PCR were performed to analyze the tyrosine hydroxylase (TH), alpha-SYN, and GATA-binding factor 2 (GATA2) transcription factor.
Results: We showed that TLR4 ablation contributes to restrain the depletion of striatal dopamine levels as well as the loss of TH+neurons and TH protein levels in the substantia nigra pars compacta (SNpc). Interestingly, we found that TLR4-null mice exhibited massive accumulation of alpha-SYN protein in the midbrain and high levels of alpha-SYN mRNA in different brain regions, such as cerebral cortex, cerebellum, striatum and hippocampus. In attempt to explore the mechanism that regulates the nigral alpha-SYN expression, the role of GATA2 transcription factor was investigated. Our data showed that the high levels of nigral alpha-SYN in TLR4-/- mice were not associated with increased levels of GATA2 protein expression.
Conclusion: Although preliminary, these results strongly suggest an important role of TLR4 in mediating dopaminergic cell loss and alpha-SYN overexpression and accumulation. Synergistic mechanisms deserve to be further investigated.
To cite this abstract in AMA style:
C. Conte, G. Mariucci, R. Cafaro. Lack of Toll-like receptor 4 is associated with accumulation of alpha-synuclein in the midbrain Parkinson’s disease mice. [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/lack-of-toll-like-receptor-4-is-associated-with-accumulation-of-alpha-synuclein-in-the-midbrain-parkinsons-disease-mice/. Accessed June 15, 2025.« Back to 2022 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/lack-of-toll-like-receptor-4-is-associated-with-accumulation-of-alpha-synuclein-in-the-midbrain-parkinsons-disease-mice/