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

  • Giuseppina Mariucci
  • Rita Pagiotti
  • Francesco Galli
  • Luigina Romani
  • Carmela Conte
Article

Abstract

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 (α-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 α-SYN protein accumulation in the midbrain along with high α-SYN mRNA levels in cerebral cortex, striatum, hippocampus, and cerebellum. Contrary to expectations, the high levels of α-SYN do not correlate with greater dopaminergic neuronal loss. The levels of nigral α-SYN protein in TLR4−/− mice further, but not significantly, increased during MPTP treatment. Contrariwise, MPTP treatment significantly induced the mRNA expression of α-SYN in examined brain regions of WT and TLR4−/− mice. Protein levels of GATA2, a transcription factor proposed to control α-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 α-SYN. However, further exploration is needed in order to establish the actual role of α-SYN in the relative absence of TLR4.

Keywords

Parkinson’s disease Toll-like receptor 4 Thyrosine hydroxylase Alpha-synuclein GATA2 

Abbreviations

α-SYN

alpha-synuclein

ASPs

α-synucleinopathies

CSF

Central nervous system

CNS

Central nervous system

DA

Dopamine

DAMPs

Danger-associated molecular patterns

PAMPs

Pathogen-associated molecular patterns

MSA

Multiple system atrophy

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PD

Parkinson’s disease

PRRs

Pattern recognition receptors

SN

Substantia nigra

SNpc

Substantia nigra pars compacta

TLRs

Toll-like receptors

TH

Tyrosine hydroxylase

TLR4−/−

TLR4-deficient mice

WT

Wild-type mice

Notes

Acknowledgements

We thank Prof Luigina Romani (University of Perugia) for the generous gift of TLR4−/− mice.

This study was supported by grants from the Fondazione Cassa di Risparmio di Perugia for Scientific and Technological Research (no. 2016.0031.021) and from the University of Perugia (Ricerca di base 2014; Ricerca di base 2015).

Compliance with Ethical Standards

Experiments were performed according to the Italian Approved Animal Welfare Assurance 245-2011-B

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesUniversity of PerugiaPerugiaItaly
  2. 2.Department of Experimental MedicineUniversity of PerugiaPerugiaItaly

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