Is multiple system atrophy an infectious disease?

Laboratory Investigation

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of insoluble, aggregated αsynuclein (αS) pathological inclusions. Multiple system atrophy (MSA) presents with extensive oligodendroglial αS pathology and additional more limited neuronal inclusions while most of the other synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies (DLB), develop αS pathology primarily in neuronal cell populations. αS biochemical alterations specific to MSA have been described but thorough examination of these unique and disease-specific protein deposits is further warranted especially given recent findings implicating the prion-like nature of synucleinopathies perhaps with distinct strain-like properties. Taking advantage of an extensive panel of antibodies that target a wide range of epitopes within αS, we investigated the distinct properties of the various types of αS inclusion present in MSA brains with comparison to DLB. Brain biochemical fractionation followed by immunoblotting revealed that the immunoreactive profiles were significantly more consistent for DLB than for MSA. Furthermore, epitope-specific immunohistochemistry varied greatly between different types of MSA αS inclusions and even within different brain regions of individual MSA brains. These studies highlight the importance of using a battery of antibodies for adequate appreciation of the various pathology in this distinct synucleinopathy. In addition, it can be posited that if the spread of pathology in MSA undergoes prion-like mechanisms, "strains" of αS aggregated conformers must be inherently unstable and readily mutable, perhaps resulting in a more stochastic progression process.

Movement Disorders, 2013

A B S T R AC T : Altered protein handling is thought to play a key role in the etiopathogenesis of Parkinson's disease (PD), as the disorder is characterized neuropathologically by the accumulation of intraneuronal protein aggregates (Lewy bodies and Lewy neurites). Attention has particularly focused on the a-synuclein protein, as it is the principal component of Lewy pathology. Moreover, point mutations in the a-synuclein gene cause rare familial forms of PD. Importantly, duplication/triplication of the wild type a-synuclein gene also cause a form of PD, indicating that increased levels of the normal a-synuclein protein is sufficient to cause the disease. Further, single nucleotide polymorphisms in the a-synuclein gene are associated with an increased risk of developing sporadic PD. Recent evidence now suggests the possibility that a-synuclein is a prion-like protein and that PD is a prion-like disease. Within cells, asynuclein normally adopts an a-helical conformation. However, under certain circumstances, the protein can undergo a profound conformational transition to a bsheet-rich structure that polymerizes to form toxic oligomers and amyloid plaques. Recent autopsy studies of patients with advanced PD who received transplantation of fetal nigral mesencephalic cells more than a decade earlier demonstrated that typical Lewy pathology had developed within grafted neurons. This suggests that a-synuclein in an aberrantly folded, b-sheet-rich form had migrated from affected to unaffected neurons. Laboratory studies confirm that a-synuclein can transfer from affected to unaffected nerve cells, where it appears that the misfolded protein can act as a template to promote misfolding of host a-synuclein. This leads to the formation of larger aggregates, neuronal dysfunction, and neurodegeneration. Indeed, recent reports demonstrate that a single intracerebral inoculation of misfolded a-synuclein can induce Lewy-like pathology in cells that can spread from affected to unaffected regions and can induce neurodegeneration with motor disturbances in both transgenic and normal mice. Further, inoculates derived from the brains of elderly a-synuclein-overexpressing transgenic mice have now been shown to accelerate the disease process when injected into the brains of young transgenic animals. Collectively, these findings support the hypothesis that a-synuclein is a prion-like protein that can adopt a self-propagating conformation that causes neurodegeneration. We propose that this mechanism plays an important role in the development of PD and provides novel targets for candidate neuroprotective therapies. V C 2013 Movement Disorder Society K e y Wo rd s : misfolded a-synuclein; b-sheet formation; Lewy-like pathology; prions; toxic oligomers There has been a surge of recent interest in the possibility that neurodegenerative diseases may be related to prion disorders. 1 The first neurodegenerative disease found to be caused by the accumulation of abnormally processed proteins was scrapie in sheep. Prion diseases in humans include Creutzfeldt-Jakob disease, Gerstmann-Str€ aussler-Scheinker disease, fatal insomnia, and kuru. The fundamental event in the biology of a prion is a conformational transition that converts the normal cellular protein (eg, cellular prion protein [PrP C ]) to a misfolded isoform (eg, PrP Sc ). These, in turn, polymerize into oligomers and amyloid fibrils that coalesce into plaques and cause neurodegeneration. 2 In this review, we provide evidence suggesting that ---

BMC Neurology, 2011

Background: Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder which affects widespread areas of the brainstem, basal ganglia and cerebral cortex. A number of proteins are known to accumulate in parkinsonian brains including ubiquitin and α-synuclein. Prion diseases are sporadic, genetic or infectious disorders with various clinical and histopathological features caused by prion proteins as infectious proteinaceous particles transmitting a misfolded protein configuration through brain tissue. The most important form is Creutzfeldt-Jakob disease which is associated with a self-propagating pathological precursor form of the prion protein that is physiologically widely distributed in the central nervous system. Discussion: It has recently been found that α-synuclein may behave similarly to the prion precursor and propagate between cells. The post-mortem proof of α-synuclein containing Lewy bodies in embryonic dopamine cells transplants in PD patient suggests that the misfolded protein might be transmitted from the diseased host to donor neurons reminiscent of prion behavior. The involvement of the basal ganglia and brainstem in the degenerative process are other congruencies between Parkinson's and Creutzfeldt-Jakob disease. However, a number of issues advise caution before categorizing Parkinson's disease as a prion disorder, because clinical appearance, brain imaging, cerebrospinal fluid and neuropathological findings exhibit fundamental differences between both disease entities. Most of all, infectiousness, a crucial hallmark of prion diseases, has never been observed in PD so far. Moreover, the cellular propagation of the prion protein has not been clearly defined and it is, therefore, difficult to assess the molecular similarities between the two disease entities. Summary: At the current state of knowledge, the molecular pathways of transmissible pathogenic proteins are not yet fully understood. Their exact involvement in the pathophysiology of prion disorders and neurodegenerative diseases has to be further investigated in order to elucidate a possible overlap between both disease categories that are currently regarded as distinct entities.

2015

α-Synuclein (α-syn) plays a central role in the pathogenesis of neurodegenerative disorders collectively known as “synucleinopathies” that include Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Understanding the underlying molecular mechanisms of neurodegenerative diseases is indispensably important because of the prevalence of these devastating conditions in the elderly population. Several findings from cell culture and in vivo experiments suggest intercellular transfer of α-syn aggregates. The concept of intracellular α-syn pathology spread was recently extended by the discovery of propagation of α-syn aggregates throughout PD brains. The resulting concept of cell-to-cell propagation of α-syn pathology comprises of its release, uptake, and subsequently seeding of intracellular α-syn aggregation in recipient cells. In this PhD thesis the methodology used to obtain synthetic mammalian prions has been used to obtain recombinant human and ...

Brain, 2013

a-Synuclein is the major component of filamentous inclusions that constitute the defining characteristic of neurodegenerative a-synucleinopathies. However, the molecular mechanisms underlying a-synuclein accumulation and spread are unclear. Here we show that intracerebral injections of sarkosyl-insoluble a-synuclein from brains of patients with dementia with Lewy bodies induced hyperphosphorylated a-synuclein pathology in wild-type mice. Furthermore, injection of fibrils of recombinant human and mouse a-synuclein efficiently induced similar a-synuclein pathologies in wild-type mice. C57BL/6J mice injected with a-synuclein fibrils developed abundant Lewy body/Lewy neurite-like pathology, whereas mice injected with soluble a-synuclein did not. Immunoblot analysis demonstrated that endogenous mouse a-synuclein started to accumulate 3 months after inoculation, while injected human a-synuclein fibrils disappeared in about a week. These results indicate that a-synuclein fibrils have prion-like properties and inoculation into wild-type brain induces a-synuclein pathology in vivo. This is a new mouse model of sporadic a-synucleinopathy and should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy.

Neurobiology of Disease, 2014

Pathogens, 2014

Prions are unique elements in biology, being able to transmit biological information from one organism to another in the absence of nucleic acids. They have been identified as self-replicating proteinaceous agents responsible for the onset of rare and fatal neurodegenerative disorders-known as transmissible spongiform encephalopathies, or prion diseases-which affect humans and other animal species. More recently, it has been proposed that other proteins associated with common neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, can self-replicate like prions, thus sustaining the spread of neurotoxic entities throughout the nervous system. Here, we review findings that have contributed to expand the prion concept, and discuss if the involved toxic species can be considered bona fide prions, including the capacity to infect other organisms, or whether these pathogenic aggregates share with prions only the capability to self-replicate.

2014

Prions are unique elements in biology, being able to transmit biological information from one organism to another in the absence of nucleic acids. They have been identified as self-replicating proteinaceous agents responsible for the onset of rare and fatal neurodegenerative disorders-known as transmissible spongiform encephalopathies, or prion diseases-which affect humans and other animal species. More recently, it has been proposed that other proteins associated with common neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, can self-replicate like prions, thus sustaining the spread of neurotoxic entities throughout the nervous system. Here, we review findings that have contributed to expand the prion concept, and discuss if the involved toxic species can be considered bona fide prions, including the capacity to infect other organisms, or whether these pathogenic aggregates share with prions only the capability to self-replicate.

2012

The Lancet Neurology, 2010

A shared neuropathological feature of idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy is the development of intracellular aggregates of α-synuclein that gradually engage increasing parts of the nervous system. The pathogenetic mechanisms underlying these neurodegenerative disorders, however, are unknown. Several studies have highlighted similarities between classic prion diseases and these neurological proteinopathies. Specifi cally, identifi cation of Lewy bodies in fetal mesencephalic neurons transplanted in patients with Parkinson's disease raised the hypothesis that α-synuclein, the main component of Lewy bodies, could be transmitted from the host brain to a graft of healthy neurons. These results and others have led to the hypothesis that a prion-like mechanism might underlie progression of synucleinopathy within the nervous system. We review experimental fi ndings showing that misfolded α-synuclein can transfer between cells and, once transferred into a new cell, can act as a seed that recruits endogenous α-synuclein, leading to formation of larger aggregates. This model suggests that strategies aimed at prevention of cell-tocell transfer of α-synuclein could retard progression of symptoms in Parkinson's disease and other synucleinopathies.