Abstract
Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal deposits observed in Parkinson’s disease and dementia with Lewy bodies. The objective of the study was to identify surface-exposed epitopes of alpha-synuclein in vitro and in vivo formed aggregates. Polyclonal immunoglobulin Y antibodies were raised against short linear peptides of the alpha-synuclein molecule. An epitope in the N-terminal region (1–10) and all C-terminal epitopes (90–140) were found to be exposed in an indirect enzyme-linked immunosorbent assay (ELISA) using recombinant monomeric, oligomeric, and fibrillar alpha-synuclein. In a phospholipid ELISA, the N-terminus and mid-region of alpha-synuclein (i.e., 1–90) were associated with phosphatidylserine and thus occluded from antibody binding. The antibodies that reacted most strongly with epitopes in the in vitro aggregates (i.e., 1–10 and epitopes between positions 90–140) also labeled alpha-synuclein inclusions in brains from transgenic (Thy-1)-h[A30P] alpha-synuclein mice and Lewy bodies and Lewy neurites in brains of patients with alpha-synucleinopathies. However, differences in reactivity were observed with the C-terminal antibodies when brain tissue from human and transgenic mice was compared. Taken together, the study shows that although similar epitopes are exposed in both in vitro and in vivo formed alpha-synuclein inclusions, structural heterogeneity can be observed between different molecular species.
Highlights
The alpha-synucleinopathies are a subset of neurodegenerative diseases that include Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and the Lewy body variant of Alzheimer’s disease (Goedert 2001)
Polyclonal immunoglobulin Y antibodies were raised against short linear peptides of the alpha-synuclein molecule
The common pathological feature of the alpha-synucleinopathies is the presence of insoluble cytoplasmic aggregates of alpha-synuclein, termed Lewy bodies and Lewy neurites (Spillantini et al 1997)
Summary
The alpha-synucleinopathies are a subset of neurodegenerative diseases that include Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and the Lewy body variant of Alzheimer’s disease (Goedert 2001). The common pathological feature of the alpha-synucleinopathies is the presence of insoluble cytoplasmic aggregates of alpha-synuclein, termed Lewy bodies and Lewy neurites (Spillantini et al 1997). In PD, the inclusions are mainly found in dopaminergic neurons in the substantia nigra and other subcortical regions, while in DLB, they are located in the cerebral cortex (Spillantini et al 1997, 1998). It has been believed that alpha-synuclein mainly exists as an intrinsically disordered protein, which adopts an alpha-helical structure upon binding to lipids via its N-terminus and central region (Davidson et al 1998)
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