Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation

Hiroaki Sekiya,Mariko Takata,Wataru Satake,Motonori Takahashi,Hinako Koga,Naonobu Futamura,Tatsushi Toda,Itaru Funakawa,Takeshi Kondo,Yasuhiro Ueno,Hisatomo Kowa,Kazuhiro Kobayashi,Motoi Kanagawa,Kenji Jinnai

doi:10.1007/s00401-019-01961-w

Abstract

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease that is characterized by varying degrees of cerebellar dysfunction and Parkinsonism. The neuropathological hallmark of MSA is alpha-synuclein (AS)-positive glial cytoplasmic inclusions (GCIs). Although severe neuronal loss (NL) is also observed in MSA, neuronal inclusions (NIs) are rare compared to GCIs, such that the pathological mechanism of NL in MSA is unclear. GCIs and NIs are late-stage pathology features relative to AS oligomers and may not represent early pathological changes in MSA. To reveal the early pathology of MSA, it is necessary to examine the early aggregation of AS, i.e., AS oligomers. Here, we adopted a proximity ligation assay (PLA) to examine the distribution of AS oligomers in brain tissue samples from patients with MSA and other diseases. Surprisingly, MSA brains showed a widespread distribution and abundant accumulation of oligomeric AS in neurons as well as oligodendrocytes of the neocortex. In several regions, oligomeric AS signal intensity was higher in cases with MSA than in cases with Parkinson’s disease. In contrast to previous studies, AS–PLA revealed abundant AS oligomer accumulation in Purkinje cells in MSA brains, identifying oligomeric AS accumulation as a possible cause of Purkinje cell loss. This wide distribution of AS oligomers in MSA brain neurons has not been described previously and indicates a pathological mechanism of NL in MSA.

Highlights

IntroductionIn addition to glial cytoplasmic inclusions (GCIs), Multiple system atrophy (MSA) is characterized by neuronal cytoplasmic inclusions (NCIs) and neuronal nuclear inclusions (NNIs) [7, 41]; those neuronal inclusions (NIs) are generally rare compared with GCIs. the pathological diagnosis of MSA emphasizes the presence of widespread GCIs [16]
Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease that is characterized by varying degrees of cerebellar dysfunction, Parkinsonism, and Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.1 3 Vol.:(0123456789)Acta Neuropathologica (2019) 137:455–466 dementia with Lewy bodies has led to the classification of these diseases as α-synucleinopathies.In addition to glial cytoplasmic inclusions (GCIs), MSA is characterized by neuronal cytoplasmic inclusions (NCIs) and neuronal nuclear inclusions (NNIs) [7, 41]; those neuronal inclusions (NIs) are generally rare compared with GCIs
In addition to GCIs, MSA is characterized by neuronal cytoplasmic inclusions (NCIs) and neuronal nuclear inclusions (NNIs) [7, 41]; those neuronal inclusions (NIs) are generally rare compared with GCIs

Summary

Introduction

In addition to GCIs, MSA is characterized by neuronal cytoplasmic inclusions (NCIs) and neuronal nuclear inclusions (NNIs) [7, 41]; those neuronal inclusions (NIs) are generally rare compared with GCIs. the pathological diagnosis of MSA emphasizes the presence of widespread GCIs [16]. MSA is considered a primary oligodendrogliopathy [39] wherein neuronal loss (NL) is the result of glial cell dysfunction. Previous studies have reported severe NL in regions with mild GCIs [17, 28] and in regions with neurons containing only mild AS aggregates [3]. Fibrillized AS does not fully explain the observed pathology in MSA

Objectives

Methods

Results