Generation and characterization of novel conformation-specific monoclonal antibodies for α-synuclein pathology

Nishant Vaikath, Nour Majbour, Katerina E. Paleologou, Mustafa T. Ardah, Esther van Dam, Wilma D.J. van de Berg, Shelley L. Forrest, Laura Parkkinen, Wei Ping Gai, Nobutaka Hattori, Masashi Takanashi, Seung Jae Lee, David M.A. Mann, Yuzuru Imai, Glenda M. Halliday, Jia Yi Li, Omar Ali El-Agnaf

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

α-Synuclein (α-syn), a small protein that has the intrinsic propensity to aggregate, is implicated in several neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are collectively known as synucleinopathies. Genetic, pathological, biochemical, and animal modeling studies provided compelling evidence that α-syn aggregation plays a key role in the pathogenesis of PD and related synucleinopathies. It is therefore of utmost importance to develop reliable tools that can detect the aggregated forms of α-syn. We describe here the generation and characterization of six novel conformation-specific monoclonal antibodies that recognize specifically α-syn aggregates but not the soluble, monomeric form of the protein. The antibodies described herein did not recognize monomers or fibrils generated from other amyloidogenic proteins including β-syn, γ-syn, β-amyloid, tau protein, islet amyloid polypeptide and ABri. Interestingly, the antibodies did not react to overlapping linear peptides spanning the entire sequence of α-syn, confirming further that they only detect α-syn aggregates. In immunohistochemical studies, the new conformation-specific monoclonal antibodies showed underappreciated small micro-aggregates and very thin neurites in PD and DLB cases that were not observed with generic pan antibodies that recognize linear epitope. Furthermore, employing one of our conformation-specific antibodies in a sandwich based ELISA, we observed an increase in levels of α-syn oligomers in brain lysates from DLB compared to Alzheimer's disease and control samples. Therefore, the conformation-specific antibodies portrayed herein represent useful tools for research, biomarkers development, diagnosis and even immunotherapy for PD and related pathologies.

Original languageEnglish
Pages (from-to)81-99
Number of pages19
JournalNeurobiology of Disease
Volume79
DOIs
Publication statusPublished - 1 Jul 2015

Fingerprint

Synucleins
Lewy Body Disease
Monoclonal Antibodies
Parkinson Disease
Pathology
Antibodies
Amyloidogenic Proteins
Abrus
Islet Amyloid Polypeptide
Multiple System Atrophy
tau Proteins
Neurites
Neurodegenerative Diseases
Immunotherapy
Epitopes
Molecular Biology
Alzheimer Disease
Proteins
Biomarkers
Enzyme-Linked Immunosorbent Assay

Keywords

  • Conformation-specific monoclonal antibodies
  • Dementia with Lewy bodies
  • Parkinson's disease
  • α-Synuclein

ASJC Scopus subject areas

  • Neurology

Cite this

Generation and characterization of novel conformation-specific monoclonal antibodies for α-synuclein pathology. / Vaikath, Nishant; Majbour, Nour; Paleologou, Katerina E.; Ardah, Mustafa T.; van Dam, Esther; van de Berg, Wilma D.J.; Forrest, Shelley L.; Parkkinen, Laura; Gai, Wei Ping; Hattori, Nobutaka; Takanashi, Masashi; Lee, Seung Jae; Mann, David M.A.; Imai, Yuzuru; Halliday, Glenda M.; Li, Jia Yi; Ali El-Agnaf, Omar.

In: Neurobiology of Disease, Vol. 79, 01.07.2015, p. 81-99.

Research output: Contribution to journalArticle

Vaikath, N, Majbour, N, Paleologou, KE, Ardah, MT, van Dam, E, van de Berg, WDJ, Forrest, SL, Parkkinen, L, Gai, WP, Hattori, N, Takanashi, M, Lee, SJ, Mann, DMA, Imai, Y, Halliday, GM, Li, JY & Ali El-Agnaf, O 2015, 'Generation and characterization of novel conformation-specific monoclonal antibodies for α-synuclein pathology', Neurobiology of Disease, vol. 79, pp. 81-99. https://doi.org/10.1016/j.nbd.2015.04.009
Vaikath, Nishant ; Majbour, Nour ; Paleologou, Katerina E. ; Ardah, Mustafa T. ; van Dam, Esther ; van de Berg, Wilma D.J. ; Forrest, Shelley L. ; Parkkinen, Laura ; Gai, Wei Ping ; Hattori, Nobutaka ; Takanashi, Masashi ; Lee, Seung Jae ; Mann, David M.A. ; Imai, Yuzuru ; Halliday, Glenda M. ; Li, Jia Yi ; Ali El-Agnaf, Omar. / Generation and characterization of novel conformation-specific monoclonal antibodies for α-synuclein pathology. In: Neurobiology of Disease. 2015 ; Vol. 79. pp. 81-99.
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