The etiology and pathogenesis of Parkinson’s disease (PD) are still unclear. However, multiple lines of evidence implicate Toll Like Receptor 4 (TLR4) as a concurring factor in inflammation and neuronal death. Conversely, in a model of atypical parkinsonism, TLR4 can promote α-SYN clearance and to be associated with a neuroprotective mechanism. The current study aims to establish the potential role of TLR4 in acute 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-HCl (MPTP) mouse model of PD by using TLR4-deficient mice (TLR4-/-) and their wild type littermates (WT). Seven days post-MPTP intoxication, mice were sacrificed and the brains were dissected to isolate cerebral cortex, striatum, hippocampus and midbrain region. Immunohistochemical analysis of tyrosine hydroxylase-positive neurons (TH+) was carried out in Substantia Nigra pars compacta (SNpc). TH and α-SYN mRNA levels were determined in all brain regions by real time PCR. α-SYN and TH protein levels were evaluated in midbrain region by western blotting analysis. MPTP treatment induced a significant depletion of nigral TH+ neurons in both WT and TLR4-/- mice. Moreover, we found that WT and TLR4-/- mice showed a different basal pattern of midbrain TH and α-SYN expression. TLR4-deficient mice showed lower TH protein levels than WT in midbrain region. Conversely, the midbrain from TLR4-deficient mice exhibited higher α-SYN protein levels compared to the same region from WT mice. Interestingly, high α-SYN mRNA levels were observed in all other brain regions from TLR4-/- mice. These findings suggested a role for TLR4 as a negative regulator of α-SYN expression. Further investigation are needed to clarify the cross-talk between TLR4 and α-SYN and the involvement of TLR4 in the pathogenesis of Parkinson’s disease.
The potential role of Toll like receptor 4 in regulating -SYN expression
CONTE, CARMELA;BECCARI, Tommaso;MARIUCCI, Giuseppina
2016
Abstract
The etiology and pathogenesis of Parkinson’s disease (PD) are still unclear. However, multiple lines of evidence implicate Toll Like Receptor 4 (TLR4) as a concurring factor in inflammation and neuronal death. Conversely, in a model of atypical parkinsonism, TLR4 can promote α-SYN clearance and to be associated with a neuroprotective mechanism. The current study aims to establish the potential role of TLR4 in acute 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-HCl (MPTP) mouse model of PD by using TLR4-deficient mice (TLR4-/-) and their wild type littermates (WT). Seven days post-MPTP intoxication, mice were sacrificed and the brains were dissected to isolate cerebral cortex, striatum, hippocampus and midbrain region. Immunohistochemical analysis of tyrosine hydroxylase-positive neurons (TH+) was carried out in Substantia Nigra pars compacta (SNpc). TH and α-SYN mRNA levels were determined in all brain regions by real time PCR. α-SYN and TH protein levels were evaluated in midbrain region by western blotting analysis. MPTP treatment induced a significant depletion of nigral TH+ neurons in both WT and TLR4-/- mice. Moreover, we found that WT and TLR4-/- mice showed a different basal pattern of midbrain TH and α-SYN expression. TLR4-deficient mice showed lower TH protein levels than WT in midbrain region. Conversely, the midbrain from TLR4-deficient mice exhibited higher α-SYN protein levels compared to the same region from WT mice. Interestingly, high α-SYN mRNA levels were observed in all other brain regions from TLR4-/- mice. These findings suggested a role for TLR4 as a negative regulator of α-SYN expression. Further investigation are needed to clarify the cross-talk between TLR4 and α-SYN and the involvement of TLR4 in the pathogenesis of Parkinson’s disease.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
