Abstract
Pathology consisting of intracellular aggregates of alpha-Synuclein (α-Syn) spread through the nervous system in a variety of neurodegenerative disorders including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The discovery of structurally distinct α-Syn polymorphs, so-called strains, supports a hypothesis where strain-specific structures are templated into aggregates formed by native α-Syn. These distinct strains are hypothesised to dictate the spreading of pathology in the tissue and the cellular impact of the aggregates, thereby contributing to the variety of clinical phenotypes. Here, we present evidence of a novel α-Syn strain induced by the multiple system atrophy-associated oligodendroglial protein p25α. Using an array of biophysical, biochemical, cellular, and in vivo analyses, we demonstrate that compared to α-Syn alone, a substoichiometric concentration of p25α redirects α-Syn aggregation into a unique α-Syn/p25α strain with a different structure and enhanced in vivo prodegenerative properties. The α-Syn/p25α strain induced larger inclusions in human dopaminergic neurons. In vivo, intramuscular injection of preformed fibrils (PFF) of the α-Syn/p25α strain compared to α-Syn PFF resulted in a shortened life span and a distinct anatomical distribution of inclusion pathology in the brain of a human A53T transgenic (line M83) mouse. Investigation of α-Syn aggregates in brain stem extracts of end-stage mice demonstrated that the more aggressive phenotype of the α-Syn/p25α strain was associated with an increased load of α-Syn aggregates based on a Förster resonance energy transfer immunoassay and a reduced α-Syn aggregate seeding activity based on a protein misfolding cyclic amplification assay. When injected unilaterally into the striata of wild-type mice, the α-Syn/p25α strain resulted in a more-pronounced motoric phenotype than α-Syn PFF and exhibited a “tropism” for nigro-striatal neurons compared to α-Syn PFF. Overall, our data support a hypothesis whereby oligodendroglial p25α is responsible for generating a highly prodegenerative α-Syn strain in multiple system atrophy.
Highlights
Multiple system atrophy (MSA), along with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative disorders
The three synucleinopathies PD, DLB, and MSA share the progressive development of α-Syn aggregate-containing cytoplasmic inclusions, the histopathology in MSA exhibits a range of special characteristics
The most recognised feature is that the burden of α-Syn inclusion pathology is larger in MSA than in PD and DLB, and the cytoplasmic inclusions predominantly reside in oligodendrocytes [17, 36, 66]
Summary
Multiple system atrophy (MSA), along with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative disorders They share the development of intracellular inclusions containing aggregates of the nerve cell protein alpha-Synuclein (α-Syn) and are often collectively referred to as synucleinopathies [31]. MSA brain extracts and in particular the detergent-insoluble fraction containing the α-Syn filaments are more potent seeds of α-Syn aggregation in cellular and in vivo models [79, 89, 108, 114, 115] This potency can be propagated in laboratory animals and is one reason why MSA has been proposed to represent a distinct prion-like disease [79, 108, 114, 115]. Mounting evidence supports that the α-Syn aggregation in oligodendrocytes represents the key to MSA brain extracts being potent inducers of α-Syn aggregation in disease models [77]
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