Neurotoxicity Research

, Volume 16, Issue 3, pp 238–254

Mutant α-Synuclein Overexpression Mediates Early Proinflammatory Activity

  • Xiaomin Su
  • Howard J. Federoff
  • Kathleen A. Maguire-Zeiss
Article

DOI: 10.1007/s12640-009-9053-x

Cite this article as:
Su, X., Federoff, H.J. & Maguire-Zeiss, K.A. Neurotox Res (2009) 16: 238. doi:10.1007/s12640-009-9053-x

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.

Keywords

Dopaminergic neurons Parkinson’s disease Neurodegeneration Proinflammatory molecules 

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

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Xiaomin Su
    • 1
    • 2
    • 3
  • Howard J. Federoff
    • 1
    • 4
    • 5
  • Kathleen A. Maguire-Zeiss
    • 1
    • 6
  1. 1.Center for Aging and Developmental Biology, Aab Institute for Biomedical ResearchUniversity of Rochester School of Medicine and DentistryRochesterUSA
  2. 2.Department of Microbiology and ImmunologyUniversity of Rochester School of Medicine and DentistryRochesterUSA
  3. 3.Department of NeurosurgeryUniversity of California San FranciscoSan FranciscoUSA
  4. 4.Department of NeurologyUniversity of Rochester School of Medicine and DentistryRochesterUSA
  5. 5.Department of NeurologyGeorgetown University Medical CenterWashingtonUSA
  6. 6.Department of NeuroscienceGeorgetown University Medical CenterWashingtonUSA