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Alpha-synuclein activates the classical complement pathway and mediates complement-dependent cell toxicity

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Alpha-synuclein activates the classical complement pathway and mediates complement-dependent cell toxicity. / Gregersen, Emil; Betzer, Cristine; Kim, Woojin S; Kovacs, Gergo; Reimer, Lasse; Halliday, Glenda M; Thiel, Steffen; Jensen, Poul Henning.

In: Journal of Neuroinflammation, Vol. 18, 177, 08.2021.

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@article{da1d64135bdc42579a40cac22a85980b,
title = "Alpha-synuclein activates the classical complement pathway and mediates complement-dependent cell toxicity",
abstract = "BACKGROUND: Synucleinopathies are characterized by neurodegeneration and deposition of the presynaptic protein α-synuclein in pathological protein inclusions. Growing evidence suggests the complement system not only has physiological functions in the central nervous system, but also is involved in mediating the pathological loss of synapses in Alzheimer's disease. However, it is not established whether the complement system has a similar role in the diseases Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy (MSA) that are associated with α-synuclein aggregate pathology.METHODS: To investigate if the complement system has a pathological role in synucleinopathies, we assessed the effect of the complement system on the viability of an α-synuclein expressing cell model and examined direct activation of the complement system by α-synuclein in a plate-based activation assay. Finally, we investigated the levels of the initiator of the classical pathway, C1q, in postmortem brain samples from MSA patients.RESULTS: We demonstrate that α-synuclein activates the classical complement pathway and mediates complement-dependent toxicity in α-synuclein expressing SH-SY5Y cells. The α-synuclein-dependent cellular toxicity was rescued by the complement inhibitors RaCI (inhibiting C5) and Cp20 (inhibiting C3). Furthermore, we observed a trend for higher levels of C1q in the putamen of MSA subjects than that of controls.CONCLUSION: α-Synuclein can activate the classical complement pathway, and the complement system is involved in α-synuclein-dependent cellular cytotoxicity suggesting the system could play a prodegenerative role in synucleinopathies.",
author = "Emil Gregersen and Cristine Betzer and Kim, {Woojin S} and Gergo Kovacs and Lasse Reimer and Halliday, {Glenda M} and Steffen Thiel and Jensen, {Poul Henning}",
note = "{\textcopyright} 2021. The Author(s).",
year = "2021",
month = aug,
doi = "10.1186/s12974-021-02225-9",
language = "English",
volume = "18",
journal = "Journal of Neuroinflammation",
issn = "1742-2094",
publisher = "BioMed Central",

}

RIS

TY - JOUR

T1 - Alpha-synuclein activates the classical complement pathway and mediates complement-dependent cell toxicity

AU - Gregersen, Emil

AU - Betzer, Cristine

AU - Kim, Woojin S

AU - Kovacs, Gergo

AU - Reimer, Lasse

AU - Halliday, Glenda M

AU - Thiel, Steffen

AU - Jensen, Poul Henning

N1 - © 2021. The Author(s).

PY - 2021/8

Y1 - 2021/8

N2 - BACKGROUND: Synucleinopathies are characterized by neurodegeneration and deposition of the presynaptic protein α-synuclein in pathological protein inclusions. Growing evidence suggests the complement system not only has physiological functions in the central nervous system, but also is involved in mediating the pathological loss of synapses in Alzheimer's disease. However, it is not established whether the complement system has a similar role in the diseases Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy (MSA) that are associated with α-synuclein aggregate pathology.METHODS: To investigate if the complement system has a pathological role in synucleinopathies, we assessed the effect of the complement system on the viability of an α-synuclein expressing cell model and examined direct activation of the complement system by α-synuclein in a plate-based activation assay. Finally, we investigated the levels of the initiator of the classical pathway, C1q, in postmortem brain samples from MSA patients.RESULTS: We demonstrate that α-synuclein activates the classical complement pathway and mediates complement-dependent toxicity in α-synuclein expressing SH-SY5Y cells. The α-synuclein-dependent cellular toxicity was rescued by the complement inhibitors RaCI (inhibiting C5) and Cp20 (inhibiting C3). Furthermore, we observed a trend for higher levels of C1q in the putamen of MSA subjects than that of controls.CONCLUSION: α-Synuclein can activate the classical complement pathway, and the complement system is involved in α-synuclein-dependent cellular cytotoxicity suggesting the system could play a prodegenerative role in synucleinopathies.

AB - BACKGROUND: Synucleinopathies are characterized by neurodegeneration and deposition of the presynaptic protein α-synuclein in pathological protein inclusions. Growing evidence suggests the complement system not only has physiological functions in the central nervous system, but also is involved in mediating the pathological loss of synapses in Alzheimer's disease. However, it is not established whether the complement system has a similar role in the diseases Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy (MSA) that are associated with α-synuclein aggregate pathology.METHODS: To investigate if the complement system has a pathological role in synucleinopathies, we assessed the effect of the complement system on the viability of an α-synuclein expressing cell model and examined direct activation of the complement system by α-synuclein in a plate-based activation assay. Finally, we investigated the levels of the initiator of the classical pathway, C1q, in postmortem brain samples from MSA patients.RESULTS: We demonstrate that α-synuclein activates the classical complement pathway and mediates complement-dependent toxicity in α-synuclein expressing SH-SY5Y cells. The α-synuclein-dependent cellular toxicity was rescued by the complement inhibitors RaCI (inhibiting C5) and Cp20 (inhibiting C3). Furthermore, we observed a trend for higher levels of C1q in the putamen of MSA subjects than that of controls.CONCLUSION: α-Synuclein can activate the classical complement pathway, and the complement system is involved in α-synuclein-dependent cellular cytotoxicity suggesting the system could play a prodegenerative role in synucleinopathies.

U2 - 10.1186/s12974-021-02225-9

DO - 10.1186/s12974-021-02225-9

M3 - Journal article

C2 - 34399786

VL - 18

JO - Journal of Neuroinflammation

JF - Journal of Neuroinflammation

SN - 1742-2094

M1 - 177

ER -