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

Sekiya, Hiroaki; Kowa, Hisatomo; Koga, Hinako; Takata, Masahiko; Satake, Wataru; Futamura, Naonobu; Funakawa, Itaru; Jinnai, Kenji; Takahashi, Motonori; Kondo, Takeshi; Ueno, Yoshio; Kanagawa, Motoi; Kobayashi, Kenzo; Toda, Tatsushi

doi:10.1007/s00401-019-01961-w

Cited by 57 publications

(68 citation statements)

References 43 publications

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“…However, the concentration of CSF pS129-␣Syn oligomers was sharply elevated in the postmortem CSF samples of MSA patients compared to all other clinical groups [104]. Moreover, recent studies described that o-␣Syn was abundantly distributed in neurons and oligodendrocytes in MSA brain tissues using homotypic proximity ligation assay detection [105].…”

Section: Endogenous Oligomeric αSyn Assemblies In Neurodegenerative Dmentioning

confidence: 90%

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Kayed

Dettmer

Lesné

2020

JPD

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There is growing recognition in the field of neurodegenerative diseases that mixed proteinopathies are occurring at greater frequency than originally thought. This is particularly true for three amyloid proteins defining most of these neurological disorders, amyloid-beta (A␤), tau, and alpha-synuclein (␣Syn). The coexistence and often co-localization of aggregated forms of these proteins has led to the emergence of concepts positing molecular interactions and cross-seeding between A␤, tau, and ␣Syn aggregates. Amongst this trio, ␣Syn has received particular attention in this context during recent years due to its ability to modulate A␤ and tau aggregation in vivo, to interact at a molecular level with A␤ and tau in vivo and to cross-seed tau in mice. Here we provide a comprehensive, critical, and accessible review about the expression, role and nature of endogenous soluble ␣Syn oligomers because of recent developments in the understanding of ␣Syn multimerization, misfolding, aggregation, cross-talk, spreading and cross-seeding in neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, and Huntington's disease. We will also discuss our current understanding about the relative toxicity of endogenous ␣Syn oligomers in vivo and in vitro, and introduce potential opportunities to counter their deleterious effects.

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Section: Endogenous Oligomeric αSyn Assemblies In Neurodegenerative Dmentioning

confidence: 90%

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Kayed

Dettmer

Lesné

2020

JPD

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“…95 However, it was most recently reported that also neurons in MSA show α-syn oligomers depositions. 96 A recent study showed that α-syn filaments differ in DLB and MSA. 97 PD and DLB are usually distinguished based on the symptoms, with DLB being the second most common type of dementia.…”

Section: Synapse and Neuronal Loss In Brain Disordersmentioning

confidence: 99%

Fluid Biomarkers for Synaptic Dysfunction and Loss

et al. 2020

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Synapses are the site for brain communication where information is transmitted between neurons and stored for memory formation. Synaptic degeneration is a global and early pathogenic event in neurodegenerative disorders with reduced levels of pre- and postsynaptic proteins being recognized as a core feature of Alzheimer’s disease (AD) pathophysiology. Together with AD, other neurodegenerative and neurodevelopmental disorders show altered synaptic homeostasis as an important pathogenic event, and due to that, they are commonly referred to as synaptopathies. The exact mechanisms of synapse dysfunction in the different diseases are not well understood and their study would help understanding the pathogenic role of synaptic degeneration, as well as differences and commonalities among them and highlight candidate synaptic biomarkers for specific disorders. The assessment of synaptic proteins in cerebrospinal fluid (CSF), which can reflect synaptic dysfunction in patients with cognitive disorders, is a keen area of interest. Substantial research efforts are now directed toward the investigation of CSF synaptic pathology to improve the diagnosis of neurodegenerative disorders at an early stage as well as to monitor clinical progression. In this review, we will first summarize the pathological events that lead to synapse loss and then discuss the available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, and α-syn) and emerging (eg, synaptic vesicle glycoprotein 2A and neuronal pentraxins) CSF biomarkers for synapse dysfunction, while highlighting possible utilities, disease specificity, and technical challenges for their detection.

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“…This technique offers great sensitivity because powerful rolling circle amplification is used. It also offers great selectivity because dual target recognition is used . Here, we used antibodies generated against both the N and C terminal domains of C99 in cultured cells and found that we can distinguish C99 from Ab, full‐length APP, C83, and AICD.…”

Section: Introductionmentioning

confidence: 99%

C99 selectively accumulates in vulnerable neurons in Alzheimer's disease

Pulina

Hopkins

Haroutunian

et al. 2020

Alzheimer's & Dementia

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Introduction:The levels and distribution of amyloid deposits in the brain does not correlate well with Alzheimer's disease (AD) progression. Therefore, it is likely that amyloid precursor protein and its proteolytic fragments other than amyloid b (Ab) contribute to the onset of AD. Methods:We developed a sensitive assay adapted to the detection of C99, the direct precursor of b-amyloid. Three postmortem groups were studied: control with normal and stable cognition; patients with moderate AD, and individuals with severe AD. The amount of C99 and A was quantified and correlated with the severity of AD.Results: C99 accumulates in vulnerable neurons, and its levels correlate with the degree of cognitive impairment in patients suffering from AD. In contrast, A levels are increased in both vulnerable and resistant brain areas. Discussion:These results raise the possibility that C99, rather than A plaques, is responsible for the death of nerve cells in AD.A deposits in AD brains has a poor correlation with dementia severity, loss of neural function, and cognitive impairment. 4-9 Therefore, it is possible that APP metabolites other than A make a significant contribution to AD pathophysiology. In addressing this issue, a challenge has been the inability to determine the distribution and levels of specific APP metabolites in intact cells and tissues. We have approached this problem by adapting the proximity ligation assay (PLA) for the detection of C99. In this assay, two primary antibodies recognize the target epitopes on the protein of interest. If the epitopes are in close proximity, secondary antibodies covalently bound to complementary DNA strands participate in rolling circle DNA synthesis. The DNA synthesis reaction results in a one thousand-fold amplification of the DNA circle. Fluorescently labeled complementary oligonucleotide Alzheimer's Dement. 2020;16:273-282.wileyonlinelibrary.com/journal/alz 273

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

Cited by 57 publications

References 43 publications

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Fluid Biomarkers for Synaptic Dysfunction and Loss

C99 selectively accumulates in vulnerable neurons in Alzheimer's disease

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