Lewy bodies, a defining pathological characteristic of Parkinson's disease and dementia with Lewy bodies (DLB)1,2,3,4, constitute the second most common nerve cell pathology, after the neurofibrillary lesions of Alzheimer's disease. Their formation may cause neurodegeneration, but their biochemical composition is unknown. Neurofilaments and ubiquitin are present5,6,7,8, but it is unclear whether they are major components of the filamentous material of the Lewy body9,10. Here we describe strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease11. α-Synuclein may be the main component of the Lewy body in Parkinson's disease. We also show staining for α-synuclein of Lewy bodies from DLB, indicating that the Lewy bodies from these two diseases may have identical compositions.
We studied formalin- or ethanol-fixed, paraffin-embedded tissue sections of substantia nigra from six patients with idiopathic Parkinson's disease, and from four patients with DLB (all clinically and neuropathologically confirmed cases), as well as cingulate cortex from the DLB patients (one with additional Alzheimer's disease pathology). We stained the tissue with affinity-purified, anti-α-synuclein serum PER2 (diluted 1:200)12. This antibody, raised against a synthetic peptide corresponding to residues 116-131 of human α-synuclein, specifically recognizes α-synuclein on immunoblots of human cerebral cortex extracts and does not cross-react with the related β-synuclein12. We also stained the sections with anti-β-synuclein serum PER3 (diluted 1:200) raised against a peptide corresponding to residues 99-111 of human β-synuclein12. As an absorption control we pre-incubated diluted PER2 overnight at 4 °C with 10 μM recombinant human α-synuclein. For immunohistochemistry we used avidin-biotin, with diaminobenzidine as the chromogen6,12.
Substantia nigra sections from Parkinson's disease and DLB, and cingulate cortex sections from DLB and DLB with Alzheimer's disease incubated with the α-synuclein antibody PER2 showed staining of numerous brainstem-type and cortical Lewy bodies (Figs 1 and 2). Lewy neurites, which are dystrophic processes with the same immunohistochemical staining profile as Lewy bodies, were also reactive (Figs 1a,2a). The strong staining made it difficult to distinguish between the core and the corona of the brainstem-type Lewy bodies (Figs 1, 2b). The staining was specific, and did not occur after pre-adsorption of the primary antibody with recombinant α-synuclein.
We obtained similar results with antibody PER1, raised against a synthetic peptide corresponding to residues 11-34 of human α-synuclein, indicating that full-length α-synuclein may be present in the Lewy body (data not shown). We found no specific staining of Lewy bodies or Lewy neurites with the β-synuclein antibody PER3.
We also stained tissue sections from Parkinson's disease and DLB with the ubiquitin monoclonal antibody 1510 (Chemicon, diluted 1:500)13. Double-staining of substantia nigra sections from Parkinson's disease with PER2 and 1510, showed staining of similar numbers of Lewy bodies and neurites with each antibody. Similarly, in adjacent tissue sections of substantia nigra and cingulate cortex from DLB, we found comparable numbers of Lewy bodies and neurites stained with PER2, antibody 1510 or undiluted neurofilament antibody RMO32, a monoclonal antibody to a phosphorylated epitope in the mid-sized neurofilament subunit which specifically recognizes Lewy bodies6. Cortical Lewy bodies immunoreactive to PER2 had a similar morphology to the ubiquitin- and neurofilament-positive Lewy bodies in that they had round, oval or irregular shapes and frequently displaced the nucleus to one side (Fig. 2c).
The strong α-synuclein staining of brainstem-type and cortical Lewy bodies in idiopathic Parkinson's disease and DLB shows that α-synuclein is a component of the Lewy body. In some familial cases of Parkinson's disease there is an alanine to threonine mutation at residue 53 of αsynuclein11. A major effect of this mutation may be to promote the aggregation of α-synuclein into filaments, resulting in the formation of Lewy bodies. The Parkinson's disease cases that we studied were non-familial, so at least two distinct pathogenetic mechanisms can lead to α-synuclein aggregation. α-Synuclein aggregation and Lewy-body formation may be important in the aetiologyand pathogenesis of all cases of Parkinson's disease.
As brainstem-type and cortical Lewy bodies from DLB were strongly immunoreactive for α-synuclein, α-synuclein aggregation may also underlie Lewy-body formation in this condition. The intracytoplasmic Lewy body is therefore central to the neurodegenerative process, and both Parkinson's disease and DLB may be α-synuclein diseases.
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Spillantini, M., Schmidt, M., Lee, VY. et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997). https://doi.org/10.1038/42166
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