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Novel antibodies detect additional ?-synuclein pathology in synucleinopathies: potential development for immunotherapy.

ABSTRACT: Background: Alpha-synuclein (?-Syn) aggregation is the primary characteristic of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Immunotherapy targeting ?-Syn has shown promising results in animal models of the disease. This study investigates the target specificity of three different active vaccines for pathological ?-Syn aggregates found in human brain tissue from synucleinopathies.

Methods: Guinea pigs were immunised with 3 vaccines developed by United Neuroscience, and IgG fractions purified from the resulting immune sera (IGG-1, IGG-2 or IGG-3) were used to perform immunohistochemical staining of human cases of PD, DLB and MSA. The resulting immunoreactivity was compared to a commercially available ?-Syn antibody from Novacastra (NOV) commonly used for diagnostic purposes. Images were captured from the substantia nigra (SN), temporal lobe, internal capsule, insular cortex and putamen and quantified for the percentage area with ?-Syn immunoreactivity. Lewy bodies (LB) and Lewy neurites (LN) were further analysed in PD and DLB cases.

Results: Vaccine-generated antibodies detected more ?-Syn pathology compared to NOV. The levels of ?-Syn immunoreactivity varied between brain region and disease type with IGG-3 recognising the highest levels of ?-Syn in most cases and in all brain regions that are affected early in disease progression. IGG-3 had a high recognition for glial inclusions found in MSA which are known to have a more compact conformation. Slot blot analysis confirmed the specificity of IGG-3 for native oligomers and fibrillar ?-Syn. Higher levels of ?-Syn were recognised by IGG-2 in cortical regions, and by IGG-3 in SN of PD and DLB cases. This was due to increased immunolabelling of LNs in these brain regions suggesting that IGG-2 and IGG-3 recognised additional ?-Syn pathology compared to IGG-1 and NOV. Whether the unique binding properties of the antibodies produced in guinea pigs will translate in the clinic remains to be addressed, which is the main limitation of this study.

Conclusions: These vaccines induce antibodies that bind ?-Syn oligomers and aggregates in the human brain and specifically support the choice of the vaccine generating IGG-3 (i.e. UB-312) as a candidate for clinical trials for synucleinopathies.

SUBMITTER: Nimmo JT

PROVIDER: S-EPMC7702704 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy.

Nimmo Jacqui T JT Verma Ajay A Dodart Jean-Cosme JC Wang Chang Yi CY Savistchenko Jimmy J Melki Ronald R Carare Roxana O RO Nicoll James A R JAR

Alzheimer's research & therapy 20201130 1

<h4>Background</h4>Alpha-synuclein (α-Syn) aggregation is the primary characteristic of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Immunotherapy targeting α-Syn has shown promising results in animal models of the disease. This study investigates the target specificity of three different active vaccines for pathological α-Syn aggregates found in human brain tissue from synucleinopathies.<h4>Methods</h4>Guinea pigs were ...[more]

PMID: 33256825

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Project description:Parkinson's disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may-in analogy to pGlu-Aβ peptides in Alzheimer's disease-act as a seed for pathogenic protein aggregation.

Dataset Information

Novel antibodies detect additional ?-synuclein pathology in synucleinopathies: potential development for immunotherapy.

Publications

Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy.

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