Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity

Vijay Gupta; Safa Salim; Issam Hmila; Nishant N. Vaikath; Indulekha P. Sudhakaran; Simona S. Ghanem; Nour K. Majbour; Sara A. Abdulla; Mohamed M. Emara; Houari B. Abdesselem; Tamas Lukacsovich; Daniel Erskine; Omar M.A. El-Agnaf

doi:10.1038/s41598-020-65035-8

Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity

Vijay Gupta, Safa Salim, Issam Hmila, Nishant N. Vaikath, Indulekha P. Sudhakaran, Simona S. Ghanem, Nour K. Majbour, Sara A. Abdulla, Mohamed M. Emara, Houari B. Abdesselem, Tamas Lukacsovich, Daniel Erskine, Omar M.A. El-Agnaf^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

Synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, antibody-based immunotherapy holds much promise. However, the large size of antibodies and corresponding difficulty in crossing the blood-brain barrier has limited development in this area. To overcome this issue, we engineered single-chain variable fragments (scFvs) against fibrillar α-syn, a putative disease-relevant form of α-syn. The purified scFvs showed specific activity towards α-syn fibrils and oligomers in comparison to monomers and recognized intracellular inclusions in human post-mortem brain tissue of Lewy body disease cases, but not aged controls. In vitro studies indicated scFvs inhibit the seeding of α-syn aggregation in a time-dependent manner, decreased α-syn seed-induced toxicity in a cell model of PD, and reduced the production of insoluble α-syn phosphorylated at Ser-129 (pS129-α-syn). These results suggest that our α-syn fibril-specific scFvs recognize α-syn pathology and can inhibit the aggregation of α-syn in vitro and prevent seeding-dependent toxicity. Therefore, the scFvs described here have considerable potential to be utilized towards immunotherapy in synucleinopathies and may also have applications in ante-mortem imaging modalities.

Original language	English
Article number	8137
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-65035-8
Publication status	Published - 1 Dec 2020

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Gupta, V., Salim, S., Hmila, I., Vaikath, N. N., Sudhakaran, I. P., Ghanem, S. S., Majbour, N. K., Abdulla, S. A., Emara, M. M., Abdesselem, H. B., Lukacsovich, T., Erskine, D., & El-Agnaf, O. M. A. (2020). Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity. Scientific Reports, 10(1), Article 8137. https://doi.org/10.1038/s41598-020-65035-8

@article{6ab2f40bd22649968864b58ed39ee872,

title = "Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity",

abstract = "Synucleinopathies including Parkinson{\textquoteright}s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, antibody-based immunotherapy holds much promise. However, the large size of antibodies and corresponding difficulty in crossing the blood-brain barrier has limited development in this area. To overcome this issue, we engineered single-chain variable fragments (scFvs) against fibrillar α-syn, a putative disease-relevant form of α-syn. The purified scFvs showed specific activity towards α-syn fibrils and oligomers in comparison to monomers and recognized intracellular inclusions in human post-mortem brain tissue of Lewy body disease cases, but not aged controls. In vitro studies indicated scFvs inhibit the seeding of α-syn aggregation in a time-dependent manner, decreased α-syn seed-induced toxicity in a cell model of PD, and reduced the production of insoluble α-syn phosphorylated at Ser-129 (pS129-α-syn). These results suggest that our α-syn fibril-specific scFvs recognize α-syn pathology and can inhibit the aggregation of α-syn in vitro and prevent seeding-dependent toxicity. Therefore, the scFvs described here have considerable potential to be utilized towards immunotherapy in synucleinopathies and may also have applications in ante-mortem imaging modalities.",

author = "Vijay Gupta and Safa Salim and Issam Hmila and Vaikath, {Nishant N.} and Sudhakaran, {Indulekha P.} and Ghanem, {Simona S.} and Majbour, {Nour K.} and Abdulla, {Sara A.} and Emara, {Mohamed M.} and Abdesselem, {Houari B.} and Tamas Lukacsovich and Daniel Erskine and El-Agnaf, {Omar M.A.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

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doi = "10.1038/s41598-020-65035-8",

language = "English",

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Gupta, V, Salim, S, Hmila, I, Vaikath, NN, Sudhakaran, IP, Ghanem, SS, Majbour, NK, Abdulla, SA, Emara, MM, Abdesselem, HB, Lukacsovich, T, Erskine, D & El-Agnaf, OMA 2020, 'Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity', Scientific Reports, vol. 10, no. 1, 8137. https://doi.org/10.1038/s41598-020-65035-8

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T1 - Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity

AU - Gupta, Vijay

AU - Salim, Safa

AU - Hmila, Issam

AU - Vaikath, Nishant N.

AU - Sudhakaran, Indulekha P.

AU - Ghanem, Simona S.

AU - Majbour, Nour K.

AU - Abdulla, Sara A.

AU - Emara, Mohamed M.

AU - Abdesselem, Houari B.

AU - Lukacsovich, Tamas

AU - Erskine, Daniel

AU - El-Agnaf, Omar M.A.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, antibody-based immunotherapy holds much promise. However, the large size of antibodies and corresponding difficulty in crossing the blood-brain barrier has limited development in this area. To overcome this issue, we engineered single-chain variable fragments (scFvs) against fibrillar α-syn, a putative disease-relevant form of α-syn. The purified scFvs showed specific activity towards α-syn fibrils and oligomers in comparison to monomers and recognized intracellular inclusions in human post-mortem brain tissue of Lewy body disease cases, but not aged controls. In vitro studies indicated scFvs inhibit the seeding of α-syn aggregation in a time-dependent manner, decreased α-syn seed-induced toxicity in a cell model of PD, and reduced the production of insoluble α-syn phosphorylated at Ser-129 (pS129-α-syn). These results suggest that our α-syn fibril-specific scFvs recognize α-syn pathology and can inhibit the aggregation of α-syn in vitro and prevent seeding-dependent toxicity. Therefore, the scFvs described here have considerable potential to be utilized towards immunotherapy in synucleinopathies and may also have applications in ante-mortem imaging modalities.

AB - Synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, antibody-based immunotherapy holds much promise. However, the large size of antibodies and corresponding difficulty in crossing the blood-brain barrier has limited development in this area. To overcome this issue, we engineered single-chain variable fragments (scFvs) against fibrillar α-syn, a putative disease-relevant form of α-syn. The purified scFvs showed specific activity towards α-syn fibrils and oligomers in comparison to monomers and recognized intracellular inclusions in human post-mortem brain tissue of Lewy body disease cases, but not aged controls. In vitro studies indicated scFvs inhibit the seeding of α-syn aggregation in a time-dependent manner, decreased α-syn seed-induced toxicity in a cell model of PD, and reduced the production of insoluble α-syn phosphorylated at Ser-129 (pS129-α-syn). These results suggest that our α-syn fibril-specific scFvs recognize α-syn pathology and can inhibit the aggregation of α-syn in vitro and prevent seeding-dependent toxicity. Therefore, the scFvs described here have considerable potential to be utilized towards immunotherapy in synucleinopathies and may also have applications in ante-mortem imaging modalities.

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U2 - 10.1038/s41598-020-65035-8

DO - 10.1038/s41598-020-65035-8

M3 - Article

C2 - 32424162

AN - SCOPUS:85084787624

SN - 2045-2322

VL - 10

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 8137

ER -

Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity

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