α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies

TLDR

Lewy bodies and Lewy neurites are the hallmark neuropathological features of Parkinson’s disease and dementia with Lewy bodies, composed of abnormal filamentous assemblies of unknown composition. The authors isolated Lewy body filaments using a protocol adapted from the extraction of paired helical filaments from Alzheimer’s disease brain. Immunostaining and immunoelectron microscopy show that Lewy bodies and neurites contain abundant full‑length α‑synuclein, with α‑synuclein–positive filaments outnumbering ubiquitin‑positive structures and suggesting parallel, polar α‑synuclein molecules as the major filamentous component, making α‑synuclein staining the preferred diagnostic marker.

Abstract

Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson’s disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson’s disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of α-synuclein, showing the presence of full-length or close to full-length α-synuclein. The number of α-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for α-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer’s disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-α-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended α-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that α-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.