Parkinsons Disease and other α-Synucleinopathies

Abstract Parkinson's disease is the most common movement disorder and the second most common neurodegenerative disease. Neuropathologically, it is characterized by the degeneration of nerve cells that develop filamentous inclusions in the form of Lewy bodies and Lewy neurites. Recent work has shown that rare, familial forms of Parkinson's disease are caused by missense mutations in the α-synuclein gene and that the filamentous lesions of Parkinson's disease are made of α-synuclein. The same is true of the Lewy body pathology that is associated with other neurodegenerative diseases, such as dementia with Lewy bodies. The filamentous inclusions of multiple system atrophy have also been found to be made of α-synuclein, thus providing an unexpected molecular link with Lewy body diseases. Recombinant α-synuclein assembles into filaments with similar morphologies to those found in the human diseases and with a cross-β diffraction pattern characteristic of amyloid. The related proteins β-synuclein and γ-synuclein are poor at assembling into filaments. They are not present in the pathological filamentous lesions and have not been found to be linked to genetic disease. The new work has established the α-synucleinopathies as a major class of neurodegenerative disease.