Generation and characterization of novel conformation-specific monoclonal antibodies for α-synuclein pathology.
(2015) In Neurobiology of Disease 79. p.81-99- 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... (More)
- 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. (Less)
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https://lup.lub.lu.se/record/5461249
- author
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Neurobiology of Disease
- volume
- 79
- pages
- 81 - 99
- publisher
- Elsevier
- external identifiers
-
- pmid:25937088
- wos:000356110700008
- scopus:84929996447
- pmid:25937088
- ISSN
- 0969-9961
- DOI
- 10.1016/j.nbd.2015.04.009
- language
- English
- LU publication?
- yes
- id
- 04921b0b-ef5c-4555-a5fb-d7bd3e86a06a (old id 5461249)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/25937088?dopt=Abstract
- date added to LUP
- 2016-04-01 10:30:05
- date last changed
- 2022-04-04 18:36:04
@article{04921b0b-ef5c-4555-a5fb-d7bd3e86a06a, 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.}}, author = {{Vaikath, Nishant Narayanan and Majbour, Nour K and Paleologou, Katerina E and Ardah, Mustafa T and van Dam, Esther and van de Berg, Wilma D J and Forrest, Shelley L and Parkkinen, Laura and Gai, Wei-Ping and Hattori, Nobutaka and Takanashi, Masashi and Lee, Seung-Jae and Mann, David M A and Imai, Yuzuru and Halliday, Glenda M and Li, Jia-Yi and El-Agnaf, Omar M A}}, issn = {{0969-9961}}, language = {{eng}}, pages = {{81--99}}, publisher = {{Elsevier}}, series = {{Neurobiology of Disease}}, title = {{Generation and characterization of novel conformation-specific monoclonal antibodies for α-synuclein pathology.}}, url = {{http://dx.doi.org/10.1016/j.nbd.2015.04.009}}, doi = {{10.1016/j.nbd.2015.04.009}}, volume = {{79}}, year = {{2015}}, }