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Mutant α-Synuclein Overexpression Mediates Early Proinflammatory Activity

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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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Author notes

  1. Xiaomin Su

    Present address: Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA

  2. Howard J. Federoff

    Present address: Department of Neurology, Georgetown University Medical Center, Washington, DC, USA

Authors and Affiliations

  1. Center for Aging and Developmental Biology, Aab Institute for Biomedical Research, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    Xiaomin Su, Howard J. Federoff & Kathleen A. Maguire-Zeiss

  2. Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    Xiaomin Su

  3. Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    Howard J. Federoff

  4. Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road, NW, New Research Building, EP08, Washington, DC, 20057, USA

    Kathleen A. Maguire-Zeiss

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Correspondence to Kathleen A. Maguire-Zeiss.

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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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