Association of Metallothionein-III with Oligodendroglial Cytoplasmic Inclusions in Multiple System Atrophy

D Pountney, Tracey Dickson, John Power, J Vickers, A West, Weiping Gai

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    14 Citations (Scopus)

    Abstract

    Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterised by Parkinsonian and autonomic symptoms and by widespread intracytoplasmic inclusion bodies in oligodendrocytes. These glial cytoplasmic inclusions (GCIs) are comprised of 9-10 nm filaments rich in the protein alpha-synuclein, also found in neuronal inclusion bodies associated with Parkinson's disease. Metallothioneins (MTs) are a class of low-molecular weight (6-7 kDa), cysteine-rich metal-binding proteins the expression of which is induced by heavy metals, glucocorticoids, cytokines and oxidative stress. Recent studies have shown a role for the ubiquitously expressed MT-I/II isoforms in the brain following a variety of stresses, whereas, the function of the brain-specific MT isoform, MT-III, is less clear. MT-III and MT-I/II immunostaining of post-mortem tissue in MSA and normal control human brains showed that the number of MT-III-positive cells is significantly increased in MSA in visual cortex, whereas MT-I/II isoforms showed no significant difference in the distribution of immunopositive cells in MSA compared to normal tissue. GCIs were immunopositive for MT-III, but were immunonegative for the MT-I/II isoforms. Immunofluorescence double labelling showed the co-localisation of alpha-synuclein and MT-III in GCIs in MSA tissue. In isolated GCIs, transmission electron microscopy demonstrated MT-III immunogold labelling of the amorphous material surrounding alpha-synuclein filaments in GCIs. High-molecular weight MT-III species in addition to MT-III monomer were detected in GCIs by Western analysis of the detergent-solubilised proteins of purified GCIs. These results show that MT-III, but not MT-I/II, is a specific component of GCIs, present in abnormal aggregated forms external to the alpha-synuclein filaments.

    Original languageEnglish
    Pages (from-to)115-122
    Number of pages8
    JournalNeurotoxicity Research
    Volume19
    Issue number1
    DOIs
    Publication statusPublished - Jan 2011

    Keywords

    • α-Synuclein
    • Inclusion body
    • Metallothionein
    • Multiple system atrophy

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