The Potential Role of Toll-Like Receptor 4 in Mediating Dopaminergic Cell Loss and Alpha-Synuclein Expression in the Acute MPTP Mouse Model of Parkinson's Disease

Toll-like receptors (TLRs) may have a role in Parkinson's disease (PD). In this study, we aimed at investigating the dopaminergic cell loss and alpha-synuclein (alpha-SYN) expression in TLR4-deficient mice (TLR4(-/-)) acutely exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a pharmacological PD model. TLR4 ablation restrained the number of dopaminergic neurons in the substantia nigra (SN), as assessed by tyrosine hydroxylase (TH) protein expression. Intriguingly. TLR4(-/-) mice showed massive alpha-SYN protein accumulation in the midbrain along with high alpha-SYN mRNA levels in cerebral cortex, striatum, hippocampus, and cerebellum. Contrary to expectations, the high levels of alpha-SYN do not correlate with greater dopaminergic neuronal loss. The levels of nigral alpha-SYN protein in TLR4(-/-) mice further, but not significantly, increased during MPTP treatment. Contrariwise, MPTP treatment significantly induced the mRNA expression of alpha-SYN in examined brain regions of WT and TLR4(-/-) mice. Protein levels of GATA2, a transcription factor proposed to control alpha-SYN gene expression, did not change in TLR4(-/-) mice at baseline and after MPTP treatment. These findings suggest a role for TLR4 in mediating dopaminergic cell loss and in the constitutive expression of brain alpha-SYN. However, further exploration is needed in order to establish the actual role of alpha-SYN in the relative absence of TLR4.