Association of metallothionein-III with oligodendroglial cytoplasmic inclusions in multiple system atrophy.
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.
Pountney
D L
DL
School of Medical Science, Griffith Institute of Health and Medical Research, Griffith University, Gold Coast Campus, Gold Coast, QLD 4222, Australia. d.pountney@griffith.edu.au
Dickson
T C
TC
Power
J H T
JH
Vickers
J C
JC
West
A J
AJ
Gai
W P
WP
D000368:Aged; D000369:Aged, 80 and over; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D000090023:Metallothionein 3; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology
D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins