Silver staining (Campbell-Switzer) of neuronal \u03b1-synuclein assemblies induced by multiple system atrophy and Parkinson\u2019s disease brain extracts in transgenic mice

Isabelle Lavenir,Annabelle Curry,Janice L Holton,Daniela Passarella,Masami Masuda-Suzukake,Bernardino Ghetti,Michel Goedert

doi:10.1186/s40478-019-0804-5

Abstract

Synucleinopathies [Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA)] share filamentous α-synuclein assemblies in nerve cells and glial cells. We compared the abilities of brain extracts from MSA and PD patients to induce neuronal α-synuclein assembly and neurodegeneration following intracerebral injection in heterozygous mice transgenic for human mutant A53T α-synuclein. MSA extracts were more potent than PD extracts in inducing α-synuclein assembly and in causing neurodegeneration. MSA assemblies were Campbell-Switzer- and Gallyas-silver-positive, whereas PD assemblies were only Campbell-Switzer-positive, in confirmation of previous findings. However, induced α-synuclein inclusions were invariably Campbell-Switzer-positive and Gallyas-negative, irrespective of whether MSA or PD brain extracts were injected. The α-synuclein inclusions of non-injected homozygous mice transgenic for A53T α-synuclein were also Campbell-Switzer-positive and Gallyas-negative. These findings demonstrate that transgene expression and its intracellular environment dominated over the silver staining properties of the conformers of assembled α-synuclein.

Highlights

The ordered assembly of α-synuclein into abnormal filaments defines a group of neurodegenerative diseases called synucleinopathies [18]. α-Synuclein was linked to Parkinson’s disease (PD), when a dominantly inherited missense mutation (A53T) in SNCA, the α-synuclein gene, was found to cause a familial form of PD [39]
Genome-wide association studies identified α-synuclein as a significant risk factor for idiopathic PD [32]. α-Synuclein is the major component of Lewy bodies and Lewy neurites, the intraneuronal filamentous assemblies found in all patients with PD, with or without dementia, and in patients with dementia with Lewy bodies (DLB) [44, 45]. α-Synuclein accumulates in Lewy pathology, but it can template its assembly
The defining lesion of multiple system atrophy (MSA) is the presence of α-synuclein inclusions in oligodendrocytes, the majority of which are in the form of cytoplasmic inclusions [glial cytoplasmic inclusions (GCIs) or Papp-Lantos inclusions [34, 35]]

Summary

Introduction

The ordered assembly of α-synuclein into abnormal filaments defines a group of neurodegenerative diseases called synucleinopathies [18]. α-Synuclein was linked to Parkinson’s disease (PD), when a dominantly inherited missense mutation (A53T) in SNCA, the α-synuclein gene, was found to cause a familial form of PD [39]. The ordered assembly of α-synuclein into abnormal filaments defines a group of neurodegenerative diseases called synucleinopathies [18]. Α-Synuclein is the major component of Lewy bodies and Lewy neurites, the intraneuronal filamentous assemblies found in all patients with PD, with or without dementia, and in patients with dementia with Lewy bodies (DLB) [44, 45]. Filamentous inclusions of multiple system atrophy (MSA) are made of α-synuclein [43, 47, 51]. The defining lesion of MSA is the presence of α-synuclein inclusions in oligodendrocytes, the majority of which are in the form of cytoplasmic inclusions [glial cytoplasmic inclusions (GCIs) or Papp-Lantos inclusions [34, 35]]. Inclusions comprise αsynuclein phosphorylated at S129 [1, 13]

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Conclusion