Toll-like receptors (TLRs) are identified as transmembrane proteins which can recognize a wide array of ligands, either exogenous pathogen-associated molecular patterns (PAMPs) or endogenous stress or damage-associated molecular patterns (DAMPs) and contribute to immune-relate disorders. Cumulative evidences suggest that TLRs not only have been implicated in several non-immune processes, such as neurogenesis and brain development, but can contribute to pathophysiology of several neurodegenerative conditions including alpha synucleinopathies. On the other hand, extracellular α−synuclein (α−SYN) may act as a DAMP and incite an inflammatory process via TLRs that culminate with neuronal death. Among TLRs, TLR4 seems concur, more than others, to neuronal death and inflammatory responses (1). Conversely, in a model of atypical parkinsonism, TLR4 can promote α-SYN clearance and to be associated with a neuroprotective mechanism (2). The current study aims to establish the potential role of TLR4 in acute MPTP mouse model of PD using TLR4-deficient mice (TLR4-/-) and their wild type littermates (WT). We found that MPTP intoxication induced a significant depletion of nigral TH+ neurons as well as a reduction of striatal TH mRNA and protein content in both WT and TLR4-/- mice. The MPTP-treatment also induced a significant decrease of striatal dopamine levels. Interestingly, saline-treated TLR4-/- mice exhibit in striatal and midbrain regions significantly higher mRNA and protein levels of α-SYN in comparison with WT controls. No significant changes in α-SYN occurred following MPTP treatment. Although this acute MPTP model failed to modify the levels of α-SYN, the high amount found in TLR4-/- group at baseline suggests a strong involvement of TLR4 in the mechanisms that regulate the expression and/or turnover of this protein. Further investigation needed to understand of cross-talk between TLR4 and α-SYN and the potential relationship with Parkinson's disease.
Is toll like receptor 4 involved in the mechanism which regulate expression and/or turnover of alpha-synuclein?
CONTE, CARMELA;ALBI, Elisabetta;CATALDI, SAMUELA;BECCARI, Tommaso;CODINI, Michela;MARIUCCI, Giuseppina
2015
Abstract
Toll-like receptors (TLRs) are identified as transmembrane proteins which can recognize a wide array of ligands, either exogenous pathogen-associated molecular patterns (PAMPs) or endogenous stress or damage-associated molecular patterns (DAMPs) and contribute to immune-relate disorders. Cumulative evidences suggest that TLRs not only have been implicated in several non-immune processes, such as neurogenesis and brain development, but can contribute to pathophysiology of several neurodegenerative conditions including alpha synucleinopathies. On the other hand, extracellular α−synuclein (α−SYN) may act as a DAMP and incite an inflammatory process via TLRs that culminate with neuronal death. Among TLRs, TLR4 seems concur, more than others, to neuronal death and inflammatory responses (1). Conversely, in a model of atypical parkinsonism, TLR4 can promote α-SYN clearance and to be associated with a neuroprotective mechanism (2). The current study aims to establish the potential role of TLR4 in acute MPTP mouse model of PD using TLR4-deficient mice (TLR4-/-) and their wild type littermates (WT). We found that MPTP intoxication induced a significant depletion of nigral TH+ neurons as well as a reduction of striatal TH mRNA and protein content in both WT and TLR4-/- mice. The MPTP-treatment also induced a significant decrease of striatal dopamine levels. Interestingly, saline-treated TLR4-/- mice exhibit in striatal and midbrain regions significantly higher mRNA and protein levels of α-SYN in comparison with WT controls. No significant changes in α-SYN occurred following MPTP treatment. Although this acute MPTP model failed to modify the levels of α-SYN, the high amount found in TLR4-/- group at baseline suggests a strong involvement of TLR4 in the mechanisms that regulate the expression and/or turnover of this protein. Further investigation needed to understand of cross-talk between TLR4 and α-SYN and the potential relationship with Parkinson's disease.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
