Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α‐synuclein

Abstract

Recently, alpha-synuclein was shown to be a structural component of the filaments in Lewy bodies (LBs) of Parkinson's disease (PD), dementia with LBs (DLB) as well as the LB variant of Alzheimer's disease, and this suggests that alpha-synuclein could play a mechanistic role in the pathogenesis of these disorders. To determine whether alpha-synuclein is a building block of inclusions in other neurodegenerative movement disorders, we examined brains from patients with multiple system atrophy (MSA) and detected alpha-synuclein, but not beta- or gamma-synuclein, in glial cytoplasmic inclusions (GCIs) throughout the MSA brain. In MSA white matter, alpha-synuclein-positive GCIs were restricted to oligodendrocytes, and alpha-synuclein was localized to the filaments in GCIs by immunoelectron microscopy. Finally, we demonstrated that insoluble alpha-synuclein accumulated selectively in MSA white matter with alpha-synuclein-positive GCIs. Taken together with evidence that LBs contain insoluble alpha-synuclein, our data suggest that a reduction in the solubility of alpha-synuclein may induce this protein to form filaments that aggregate into cytoplasmic inclusions, which contribute to the dysfunction or death of glial cells as well as neurons in neurodegenerative disorders with different phenotypes.

Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease

“…Their dimensions and morphology were similar to those of Lewy bodies in brain slices of patients with PD (ref. 15), as measured by electron microscopy, and of α-synuclein-containing fibrils extracted from cortical Lewy bodies characteristic of diffuse Lewy body disease 16,17 and from filamentous inclusions characteristic of multiple system atrophy 18,19 (these all presumably contain only WT). The A53T, A30P and WT in vitro fibrils were 8-10 nm in height (by atomic force microscopy) and about 10 nm in width (by electron microscopy).…”

“…To further compare the A53T fibrils produced in vitro with those extracted from brains of patients with diffuse Lewy body disease and multiple system atrophy, we used immunogold electron microscopy, with three antibodies that have been used to stain Lewy bodies in PD 4,20 and diffuse Lewy body disease brain tissue 17,20 , and cytoplasmic inclusions in multiple system atrophy brain tissue 18,19 . An antibody raised against residues 1-10 of synuclein 20 (TI17) labeled the sides of fibrillar A53T assemblies, as well as nonfibrillar, spherical A53T (Fig.…”

Genetics of Parkinsonism: a review

“…Specific oligodendroglial deposits are found at autopsy, known as glial cytoplasmic inclusions (GCIs) (Papp et al 1989). The aetiology of MSA is unknown and no autosomal dominant forms have been described ; however, pathological deposits of α-synuclein protein have been found in sporadic PD, Alzheimer's disease (AD) and MSA (Ueda et al 1993 ;Tu et al 1998). This may indicate that these neurodegenerative disorders share a similar pathogenesis.…”

“…Molecular analysis of these rare families may help to clarify the pathogenesis of the far more common sporadic forms of these diseases and how a particular genotype correlates with phenotype. It is possible that pathogenic mechanisms are shared between several neurodegenerative diseases, as mutations in the SNCA gene have been found in rare kindreds with familial Parkinsonism, while pathological deposits of α-synuclein protein have been found in sporadic PD, Alzheimers disease (AD) and Multiple System Atrophy (MSA) (Ueda et al 1993 ;Tu et al 1998). Idiopathic (or sporadic) PD is one of the commonest neurodegenerative disorders, with a clear age-dependent prevalence of 1-2 percent after age 65 years (De Rijk et al 1997).…”

Transmission of multiple system atrophy prions to transgenic mice

“…In MSA brains, argyrophilic protein deposits in oligodendrocytes are often referred to as glial cytoplasmic inclusions (GCIs) (3). Whereas neurons containing Lewy bodies composed of aggregated α-synuclein are the hallmark of PD and DLB, GCIs containing aggregated α-synuclein are pathognomonic of MSA (4)(5)(6). Transgenic (Tg) mice that overexpress wild-type (WT) human α-synuclein specifically in oligodendrocytes develop GCIlike α-synuclein deposits and exhibit loss of oligodendrocytes and neurons (7), suggesting a causal role for α-synuclein aggregates in MSA.…”