The Synucleinopathies: Twenty Years On

Abstract

In 2017, it is two hundred years since James Parkinson provided the first complete clinical description of the disease named after him, fifty years since the introduction of high-dose D,L-DOPA treatment and twenty years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson's disease and dementia with Lewy bodies as the third major synucleinopathy. Here we review our work, which led to the identification of α-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies, as well as what has happened since. Some of the experiments described were carried out in collaboration with ML Schmidt, JQ Trojanowski and VMY Lee.

Keywords: Alpha-synuclein; Parkinson’s disease; aggregate propagation; dementia with Lewy bodies; multiple system atrophy; neurodegeneration; protein aggregation.

Fig.1

Twenty years ago: Ross Jakes, Maria Grazia Spillantini and Michel Goedert (from left to right) in 1997.

Fig.2

Sequence comparison of human α-synuclein and β-synuclein. Amino acids were aligned and two gaps introduced to maximize homology. Amino acid identities between α-synuclein (α-Syn) and β-synuclein (β-Syn) are indicated by black bars. From Jakes et al. [36].

Fig.3

The α-synuclein pathology of Parkinson’s disease. Lewy bodies and Lewy neurites in the substantia nigra and several other brain regions define Parkinson’s disease at a neuropathological level. They are shown here at light (a-c) and electron microscopic (d-g) levels, labelled by α-synuclein antibodies. (a), Two pigmented nerve cells, each containing an α-synuclein-positive Lewy body (red arrows). Lewy neurites (black arrows) are also immunopositive. Scale bar, 20μm. (b), Pigmented nerve cell with two α-synuclein-positive Lewy bodies. Scale bar, 8μm. (c) α-Synuclein-positive extracellular Lewy body. Scale bar, 4μm. (d-g), Isolated filaments from the substantia nigra of patients with Parkinson’s disease are decorated with an antibody directed against the carboxy-terminal (d and e) or the amino-terminal (f,g) region of α-synuclein. The gold particles conjugated to the second antibody appear as black dots. Note the uniform decoration (d,e), and the labelling of only one filament end (f,g). Scale bar, 100 nm. From Goedert [205].

Fig.4

The α-synuclein pathology of dementia with Lewy bodies. (a,b) α-Synuclein-positive Lewy bodies and Lewy neurites in substantia nigra. Scale bar, 100μm. (c,d) α-Synuclein-positive Lewy bodies and Lewy neurites in hippocampus. Scale bar, 80μm. (e) α-Synuclein-positive Lewy body inside a Lewy neurite in substantia nigra. Scale bar, 40μm. From Spillantini et al. [58].

Fig.5

The α-synuclein pathology of multiple system atrophy. Glial cytoplasmic inclusions in several brain regions define multiple system atrophy. Similar inclusions are also present in the nuclei of some glial cells, as well as in the cytoplasm and nuclei of some nerve cells, and in nerve cell processes. Inclusions are shown here at light (a-f) and electron microscopic (g-j) levels, labelled by α-synuclein antibodies. (a-d) α-Synuclein-immunoreactive oligodendrocytes and nerve cells in white matter of pons (a,b,d) and cerebellum (c,e,f). α-Synuclein-immunoreactive oligodendrocytes and nerve cells in grey matter of pons (e) and frontal cortex (f). Arrows identify the characteristic lesions: cytoplasmic, oligodendroglial inclusions (a,f), cytoplasmic nerve cell inclusions (b), nuclear oligodendroglial inclusions (c), neuropil threads (d) and nuclear nerve cell inclusions (e). Scale bar, 33μm in (e) and 50μm in (f). (g-j), Isolated filaments from the frontal cortex and cerebellum of patients with multiple system atrophy are decorated by antibodies specific for the carboxy-terminal (g,h) and amino-terminal (i,j) regions of α-synuclein. The gold particles conjugated to the secondary antibody appear as black dots. Note the uniform decoration in (g,h) and the labelling of only one filament end in (i,j). A twisted filament is shown in (g), whereas (h) shows a straight filament. Scale bar, 100 nm. From Goedert [205].

Fig.6

Filaments extracted from the brains of patients with dementia with Lewy bodies (a) and multiple system atrophy (b) or assembled from bacterially expressed human α-synuclein (c) were decorated by an anti-α-synuclein antibody. The gold particles conjugated to the secondary antibody appear as black dots. From Goedert and Spillantini [206].

Fig.7

Human α-synuclein and its disease-causing mutations. (a), Diagram of the 140 amino acid human α-synuclein protein. The core regions of the seven amino-terminal repeats are shown as blue bars. (b), An increase in gene dosage (duplication or triplication) of the chromosomal region containing SNCA or missense mutations in SNCA cause dominantly inherited forms of Parkinson’s disease and dementia with Lewy bodies. (c), The repeats (residues 7–87) of human α-synuclein are shown, with disease-causing missense mutations (A30P, E46K, H50Q, G51D, A53E and A53T) given as blue letters. Amino acids that are identical in at least five of the seven repeats are shaded in blue.