The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to α-synuclein inclusions

Radford, Rowan A. W.; Rcom-H'cheo-Gauthier, Alex; Wong, Mathew Brendan; Eaton, Emma D.; Quilty, Marian C; Blizzard, CL; Norazit, Anwar; Meedeniya, Adrian Cuda Banda; Vickers, James C.; Gai, Wei; Guillemin, Gilles J.; West, Adrian K.; Dickson, Tracey C.; Chung, Roger S.; Pountney, Dean L.

doi:10.1016/j.mcn.2015.02.015

Cited by 51 publications

(73 citation statements)

References 67 publications

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“…Many mechanisms for the development and propagation of MSA have been postulated, including impaired elimination of α-synuclein within the cell, [41][42][43][44] mitochondrial dysfunction, 32,33,45,46 direct toxicity of α-synuclein, 47 oxidative stress, 48 and neuroinflammation. 49,50 More recently, there are also data that implicate a prion-like propagation of MSA. 51 We are hopeful that genetic associations may give us further clues into the pathogenesis of MSA, as well as targets for therapeutic interventions.…”

Section: Resultsmentioning

confidence: 99%

Understanding Multiple System Atrophy—Could Genetics Lead the Way?

Sklerov¹,

Waters²

2016

US Neurology

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Multiple system atrophy (MSA) is a progressive, adult-onset, neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia, autonomic failure, and corticospinal tract dysfunction. It is considered a rare disease, similar in frequency to the more well-known neurodegenerative disease amyotrophic lateral sclerosis or Lou Gehrig’s disease. Though MSA has not traditionally been considered a genetic disease, new evidence is emerging supporting some genetic predisposition in many patients. In this short review, we will discuss advances in the knowledge of genetics in MSA and how this has furthered our understanding of the pathophysiology of the disease. There is still much unknown about this disease, but some of the recent advances made in MSA genetics may give important clues to understanding the pathogenesis and treatment of this disease.

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Section: Resultsmentioning

confidence: 99%

Understanding Multiple System Atrophy—Could Genetics Lead the Way?

Sklerov¹,

Waters²

2016

US Neurology

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“…As-trocytes are able to accumulate α-syn in MSA and in tg mouse models (Mandler et al, 2015; Nakamura et al, 2016), and stimulate the release of pro-inflammatory cytokines (Lee et al, 2010). MSA brains exhibit widespread astrogliosis (Schwarz et al, 1996) correlated to the presence of nearby GCI-positive oligodendrocytes (Radford et al, 2015), suggesting that localized presence of extracellular α-syn may underlie the astrocytic pathology in MSA. Additionally, microglia phagocytize α-syn (Lee et al, 2008b; Park et al, 2008) and also release pro-in-flammatory factors and reactive oxygen species in response to extracellular α-syn (Beraud et al, 2013; Fellner et al, 2013).…”

Section: The Neuropathology Of Msamentioning

confidence: 99%

The neuropathology of multiple system atrophy and its therapeutic implications

Valera

Masliah

2018

Autonomic Neuroscience

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Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by the abnormal accumulation of toxic forms of the synaptic protein alpha-synuclein (α-syn) within oligodendrocytes and neurons. The presence of α-syn within oligodendrocytes in the form of glial cytoplasmic inclusions is the diagnostic hallmark of MSA. However, it has been postulated that α-syn is produced in neurons and propagates to oligodendrocytes, where unknown mechanisms lead to its accumulation. The presence of α-syn within neurons in MSA has not been so extensively studied, but it may shed light into neuropathological mechanisms leading to oligodendroglial accumulation. Here we summarize the principal neuropathological events of MSA, and discuss how a deeper knowledge of these mechanisms may help develop effective therapies targeting α-syn accumulation and spreading.

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“…Additionally, recent work has shown that certain α-syn species can operate in a prion-like manner to auto-catalyze misfolding and aggregation, thereby resulting in neurotoxicity and neurodegeneration [60]. Radford et al (2015) reported glial inclusion body formation in mice injected with dispersed GCI material [63]. Recasens et al (2014) showed that human LB enriched fractions were able to induce PD-like pathology in macaque monkeys [64].…”

Section: α-Synuclein and Disease Spreadmentioning

confidence: 99%

“…As described previously, the oligodendroglial α-syn deposits observed in MSA are likely derived from an external source. Selective accumulation of α-syn occurred in primary astrocyte/oligodendrocyte co-cultures treated with α-syn protein [63] and cargo transport between neurons and oligodendrocytes and astrocytes has been demonstrated [87]. α-Syn was also found in vesicular structures (40 nm) in astrocytic endfeet of post-mortem MSA patient tissue with long disease duration, while α-syn pathology is observed both in astrocytes and Bergmann glia in α-synucleinopathies [88,89,90].…”

Section: Extracellular α-Syn Secretion and Uptakementioning

confidence: 99%

“…α-Syn also functions as a chemo-attractant, recruiting microglia to damaged cells [129]. Microglia are particularly sensitive to exogenous α-syn and it has been found to elicit pro-inflammatory and phagocytic responses in vitro via Toll-like receptor (TLR)-dependent pathways, such as TLR4, in addition to scavenger receptors, such as CD36 [63,130,131,132,133,134,135,136,137]. It is conceivable that α-syn could attract and activate microglia which fail to completely clear α-syn and potentially cause neurodegeneration themselves through an excessive pro-inflammatory response [135].…”

Section: Microgliamentioning

confidence: 99%

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Potential Modes of Intercellular α-Synuclein Transmission

Valdinocci

Radford

Siow

et al. 2017

IJMS

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Intracellular aggregates of the α-synuclein protein result in cell loss and dysfunction in Parkinson's disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as α-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby α-synuclein aggregates mediate cytotoxicity also remain to be fully elucidated. However, recent studies have implicated the cell-to-cell spread of α-synuclein as the major mode of disease propagation between brain regions during disease progression. Here, we review the current evidence for different modes of α-synuclein cellular release, movement and uptake, including exocytosis, exosomes, tunneling nanotubes, glymphatic flow and endocytosis. A more detailed understanding of the major modes by which α-synuclein pathology spreads throughout the brain may provide new targets for therapies that halt the progression of disease.

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The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to α-synuclein inclusions

Cited by 51 publications

References 67 publications

Understanding Multiple System Atrophy—Could Genetics Lead the Way?

Understanding Multiple System Atrophy—Could Genetics Lead the Way?

The neuropathology of multiple system atrophy and its therapeutic implications

Potential Modes of Intercellular α-Synuclein Transmission

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