Diffuse Intracytoplasmic Ganglionic Inclusions (Lewy Type) Associated with Progressive Dementia and Quadriparesis in Flexion

Okazaki, Haruo; Lipkin, Lewis E.; Aronson, Stanley M

doi:10.1097/00005072-196104000-00007

Cited by 259 publications

(114 citation statements)

References 2 publications

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“…Abundant Lewy bodies and Lewy neurites in cerebral cortex are the defining neuropathological characteristics of dementia with Lewy bodies (DLB), a common late-life dementia that is clinically similar to Alzheimer's disease (6)(7)(8). Cortical Lewy bodies are spherical intracytoplasmic inclusions that lack a distinctive core and halo, but that are made of filaments with morphologies similar to those of Lewy bodies from brainstem areas (6, 7).…”

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confidence: 99%

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

Spillantini

Crowther

Jakes

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

2,843

2,220

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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 aminoterminal and carboxyl-terminal sequences of ␣-synuclein, showing the presence of full-length or close to full-length ␣-synuclein. The number of ␣-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for ␣-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-␣-synuclein antibodies. The morphologies of the 5-to 10-nm filaments and their staining characteristics suggest that extended ␣-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that ␣-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.

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mentioning

confidence: 99%

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

Spillantini

Crowther

Jakes

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

2,843

2,220

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“…Neuropathologically, it is defined by nerve cell loss in the substantia nigra and other brain regions and the presence there of Lewy bodies and Lewy neurites (1,2). Abundant Lewy bodies and Lewy neurites in cerebral cortex are also the defining neuropathological characteristics of dementia with Lewy bodies (DLB), a common late-life dementia that is clinically similar to Alzheimer's disease (3,4). Ultrastructurally, Lewy bodies and Lewy neurites are composed of filamentous and granular material (5).…”

mentioning

confidence: 99%

Fiber diffraction of synthetic α-synuclein filaments shows amyloid-like cross-β conformation

Serpell

Berriman

Jakes

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

732

696

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Filamentous inclusions made of ␣-synuclein constitute the defining neuropathological characteristic of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Rare familial cases of Parkinson's disease are associated with mutations A53T and A30P in ␣-synuclein. We report here the assembly properties and secondary structure characteristics of recombinant ␣-synuclein. Carboxy-terminally truncated human ␣-synuclein (1-87) and (1-120) showed the fastest rates of assembly, followed by human A53T ␣-synuclein, and rat and zebra finch ␣-synuclein. Wild-type human ␣-synuclein and the A30P mutant showed slower rates of assembly. Upon shaking, filaments formed within 48 h at 37°C. The related proteins ␤-and ␥-synuclein only assembled after several weeks of incubation. Synthetic human ␣-synuclein filaments were decorated by an antibody directed against the carboxy-terminal 10 amino acids of ␣-synuclein, as were filaments extracted from dementia with Lewy bodies and multiple system atrophy brains. Circular dichroism spectroscopy indicated that ␣-synuclein undergoes a conformational change from random coil to ␤-sheet structure during assembly. X-ray diffraction and electron diffraction of the ␣-synuclein assemblies showed a cross-␤ conformation characteristic of amyloid.

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“…Lewy bodies and Lewy neurites also are found in other brain regions and are associated with dementia with Lewy bodies, a common late-life dementia that is clinically similar to Alzheimer's disease (5), in Lewy body variant of Alzheimer's disease (6), and in multiple system atrophy. Structurally, typical Lewy bodies appear as intracytoplasmic inclusions, 5-25 m in diameter with a dense eosinophilic core and clearer surrounding halo.…”

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confidence: 99%

Metal-triggered Structural Transformations, Aggregation, and Fibrillation of Human α-Synuclein

Uversky¹,

Li²,

Fink³

2001

Journal of Biological Chemistry

1,006

600

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Parkinson's disease involves the aggregation of ␣-synuclein to form fibrils, which are the major constituent of intracellular protein inclusions (Lewy bodies and Lewy neurites) in dopaminergic neurons of the substantia nigra. Occupational exposure to specific metals, especially manganese, copper, lead, iron, mercury, zinc, aluminum, appears to be a risk factor for Parkinson's disease based on epidemiological studies. Elevated levels of several of these metals have also been reported in the substantia nigra of Parkinson's disease subjects. We examined the effect of various metals on the kinetics of fibrillation of recombinant ␣-synuclein and in inducing conformational changes, as monitored by biophysical techniques. Several di-and trivalent metal ions caused significant accelerations in the rate of ␣-synuclein fibril formation. Aluminum was the most effective, along with copper(II), iron(III), cobalt(III), and manganese(II). The effectiveness correlated with increasing ion charge density. A correlation was noted between efficiency in stimulating fibrillation and inducing a conformational change, ascribed to formation of a partially folded intermediate. The potential for ligand bridging by polyvalent metal ions is proposed to be an important factor in the metal-induced conformational changes of ␣-synuclein. The results indicate that low concentrations of some metals can directly induce ␣-synuclein fibril formation.

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Diffuse Intracytoplasmic Ganglionic Inclusions (Lewy Type) Associated with Progressive Dementia and Quadriparesis in Flexion

Cited by 259 publications

References 2 publications

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

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

Fiber diffraction of synthetic α-synuclein filaments shows amyloid-like cross-β conformation

Metal-triggered Structural Transformations, Aggregation, and Fibrillation of Human α-Synuclein

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