Abstract
Microglia provide immune surveillance for the brain through both the removal of cellular debris and protection against infection by microorganisms and “foreign” molecules. Upon activation, microglia display an altered morphology and increased expression of proinflammatory molecules. Increased numbers of activated microglia have been identified in a number of neurodegenerative diseases including Parkinson’s disease (PD). What remains to be determined is whether activated microglia result from ongoing cell death or are involved in disease initiation and progression. To address this question we utilized a transgenic mouse model that expresses a mutated form of a key protein involved in Parkinson’s disease, α-synuclein. Herein, we report an increase in activated microglia and proinflammatory molecules in 1-month-old transgenic mice well before cell death occurs in this model. Frank microglial activation is resolved by 6 months of age while a subset of proinflammatory molecules remain elevated for 12 months. Both tyrosine hydroxylase mRNA expression and α-synuclein protein are decreased in the striatum of older animals evidence of dystrophic neuritic projections. To determine whether mutated α-synuclein could directly activate microglia primary microglia-enriched cell cultures were treated with exogenous mutated α-synuclein. The data reveal an increase in activated microglia and proinflammatory molecules due to direct interaction with mutated α-synuclein. Together, these data demonstrate that mutated α-synuclein mediates a proinflammatory response in microglia and this activity may participate in PD pathogenesis.
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Abbreviations
- DAB:
-
3,3′-Diaminobenzidine
- DM SYN:
-
Double-mutant human α-synuclein protein
- ERK:
-
Extracellular signal regulated kinase
- Iba1:
-
Ionized calcium-binding adaptor molecule
- LBs:
-
Lewy Bodies
- LPS:
-
Lipopolysaccharide
- MEM:
-
Minimum essential medium
- NaCl:
-
Sodium chloride
- NTG:
-
Non-transgenic
- PBS:
-
Phosphate-buffered saline
- PD:
-
Parkinson’s disease
- SN:
-
Substantia nigra
- STR:
-
Striatum
- SYN:
-
α-Synuclein
- SYNDM+/+:
-
Homozygous double-mutant α-synuclein transgenic mice
- SYNWT+/+:
-
Homozygous wild type α-synuclein transgenic mice
- WT SYN:
-
Wild-type human α-synuclein protein
- TE buffer:
-
Tris-EDTA buffer
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Acknowledgments
We thank Catherine Dunn and Qiong Liu for technical assistance with the synuclein subcloning and protein preparations and Landa Prifti for assistance with animal colony maintenance. This work was supported by DAMD17-03-1-0009 to H.J.F. and R01ES014470 to K.M.Z.
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Su, X., Federoff, H.J. & Maguire-Zeiss, K.A. Mutant α-Synuclein Overexpression Mediates Early Proinflammatory Activity. Neurotox Res 16, 238–254 (2009). https://doi.org/10.1007/s12640-009-9053-x
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DOI: https://doi.org/10.1007/s12640-009-9053-x