Heterogeneity of Nigral and Cortical Lewy Bodies Differentiated by Amplified Triple-Labeling for Alpha-Synuclein, Ubiquitin, and Thiazin Red

Sakamoto, Masae; Uchihara, Toshiki; Hayashi, Masaharu; Nakamura, Ayako; Kikuchi, Etsuko; Mizutani, Toshio; Mizusawa, Hidehiro; Hirai, Shunsaku

doi:10.1006/exnr.2002.7961

Cited by 46 publications

(40 citation statements)

References 41 publications

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“…They hypothesized that the spectrum of ␣-SYN inclusions represent different stages in the evolution of LB, the cloud-like ␣-SYN structures represent an early stage; these evolve to more compact structures that may become tagged with ubiquitin and could be interpreted as pale bodies, which become more condensed with a halo to form the classic LB. The data suggest that pale bodies can progress to become classical LB (14,26).…”

Section: Description and Composition Of Lb Light Microscopymentioning

confidence: 90%

“…LB in the neocortex typically lack a halo (14) and may be inconspicuous with hematoxylin͞eosin. However, Sakamoto et al (26) immunolabeled for ␣-SYN in PD brains and found that Ϸ36% of nigral LB lacked peripheral accentuation of ␣-SYN, and 31% of LB in the cingulate cortex had this peripheral ␣-SYN accentuation. Gómez-Tortosa et al (14) immunolabeled for ␣-SYN and ubiquitin in the SN and cortical regions from patients with LBD and noted a spectrum of intracytoplasmic inclusions from diffuse or ''cloud-like'' ␣-SYN staining, which were typically ubiquitin-negative and not apparent with hematoxylin͞eosin staining, to pale bodies, which had variable immunolabeling for ubiquitin, to classical LB with a halo, usually with ␣-SYN labeling in the halo and ubiquitin labeling in the core.…”

Section: Description and Composition Of Lb Light Microscopymentioning

confidence: 99%

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Lewy bodies

Shults

2006

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

408

277

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Lewy bodies (LB) in the substantia nigra are a cardinal pathological feature of Parkinson's disease, but they occur in a number of neurodegenerative diseases and can be widespread in the nervous system. The characteristics, locations, and composition of LB are reviewed, with particular attention to ␣-synuclein (␣-SYN), which appears to be the major component of LB. The propensity for ␣-SYN, a presynaptic protein widely expressed in the brain, to aggregate is because of an amyloidogenic central region. The factors that favor the aggregation of ␣-SYN and mechanisms of toxicity are examined, and a mechanism through which aggregates of ␣-SYN could induce mitochondrial dysfunction and͞or release of proapoptotic molecules is proposed.

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Section: Description and Composition Of Lb Light Microscopymentioning

confidence: 90%

Section: Description and Composition Of Lb Light Microscopymentioning

confidence: 99%

Lewy bodies

Shults

2006

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

408

277

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“…At the next stage, these diffuse inclusions evolve to more compact structures that may become tagged with ubiquitin and form pale bodies. Finally, these pale bodies become more condensed with a halo to produce the classic LB [106,110]. Ultrastructural analysis of substantia nigra in PD using an electron microscopy revealed the existence of two types of LBs, the classical (and more common) LB with a central core and a halo when observed with light microscopy and the LB of uniform density as seeing with light microscopy [111,112].…”

Section: Morphologies and Composition Of -Synuclein Containing Inclusmentioning

confidence: 97%

α-Synuclein Misfolding and Neurodegenerative Diseases

Uversky

2008

CPPS

185

159

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Alpha-synuclein is an abundant presynaptic brain protein, misfolding, aggregation and fibrillation of which are implicated as critical factors in several neurodegenerative diseases. The list of the well-known synucleinopathies includes such devastating disorders as Parkinson's disease, Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, dementia with Lewy bodies, multiple system atrophy, and neurodegeneration with brain iron accumulation type I. The precise functions of alpha-synuclein remain elusive, but there are evidence indicating its involvement in regulation vesicular release and/or turnover and synaptic function in the central nervous system. It might play a role in neuronal plasticity responses, bind fatty acids, regulate certain enzymes, transporters, and neurotransmitter vesicles, be involved in neuronal survival and even can act as a molecular chaperone. Structurally, alpha-synuclein is an illustrative member of the rapidly growing family of natively unfolded (or intrinsically disordered) proteins and considerable knowledge has been accumulated about its structural properties and conformational behavior. The molecular mechanisms underlying misfolding, aggregation and fibrillation of alpha-synuclein and the role of various environmental and genetic factors in stimulation and inhibition of these processes are relatively well understood. Here, the main structural features of alpha-synuclein, its functions, and involvement in various human diseases are summarized providing a foundation for better understanding of the biochemistry, biophysics and neuropathology of alpha-synuclein aggregation.

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“…The fibrillary components in the central portion of the LB is suggested to undergo conformational changes revealing different epitopes in relation to LB evolution. 17 The precise biochemical components of LB are still unknown, but in addition to AS and Ub, a large number of proteins, including synphylin (an AS-interactive protein), enzymes, lipids, redox-active iron, etc., have been identified. 6,16,18 Ultrastructurally, LB are composed of radially arranged 7-to 20-nm intermediate filaments associated with granular electron-dense material and vesicular structures, the core showing densely packed filaments and dense granular material.…”

Section: Neuropathology Of Lewy Body Diseasesmentioning

confidence: 99%

Neuropathological spectrum of synucleinopathies

Ka¹

2003

Mov Disord.

297

168

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Synucleinopathies comprise a diverse group of neurodegenerative proteinopathies that share common pathological lesions composed of aggregates of conformational and posttranslational modifications of alpha-synuclein in selected populations of neurons and glia. Abnormal filamentous aggregates of misfolded alpha-synuclein protein are the major components of Lewy bodies, dystrophic (Lewy) neurites, and the Papp-Lantos filaments in oligodendroglia and neurons in multiple system atrophy linked to degeneration of affected brain regions. The synucleinopathies include (1) Lewy body disorders and dementia with Lewy bodies, (2) multiple system atrophy (MSA), and (3) Hallervorden-Spatz disease. (1) The pathological diagnosis of Lewy body disorders and dementia with Lewy bodies is established by validated consensus criteria based on semiquantitative assessment of subcortical and cortical Lewy bodies as their common hallmarks. They are accompanied by subcortical multisystem degeneration with neuronal loss and gliosis with or without Alzheimer pathologic state. Lewy bodies also occur in numerous other disorders, including pure autonomic failure, neuroaxonal dystrophies, and various amyloidoses and tauopathies. (2) Multiple system atrophy, a sporadic, adult-onset degenerative movement disorder of unknown cause, is characterized by alpha-synuclein-positive glial cytoplasmic and rare neuronal inclusions throughout the central nervous system associated with striatonigral degeneration, olivopontocerebellar atrophy, and involvement of medullar and spinal autonomic nuclei. (3) In neurodegeneration with brain iron accumulation type I, or Hallervorden-Spatz disease, alpha-synuclein is present in axonal spheroids and glial and neuronal inclusions. While the identity of the major components of Lewy bodies suggests that a pathway leading from normal soluble to abnormal misfolded filamentous proteins is central for their pathogenesis, regardless of the primary disorder, there are conformational differences in alpha-synuclein between neuronal and glial aggregates, showing nonuniform mapping for its epitopes. Despite several cellular and transgenic models, it is not clear whether inclusion body formation is an adaptive/neuroprotective or a pathogenic reaction/process generated in response to different, mostly undetermined, functional triggers linked to neurodegeneration.

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Heterogeneity of Nigral and Cortical Lewy Bodies Differentiated by Amplified Triple-Labeling for Alpha-Synuclein, Ubiquitin, and Thiazin Red

Cited by 46 publications

References 41 publications

Lewy bodies

Lewy bodies

α-Synuclein Misfolding and Neurodegenerative Diseases

Neuropathological spectrum of synucleinopathies

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Heterogeneity of Nigral and Cortical Lewy Bodies Differentiated by Amplified Triple-Labeling for Alpha-Synuclein, Ubiquitin, and Thiazin Red

Cited by 46 publications

References 41 publications

Lewy bodies

Lewy bodies

&#945;-Synuclein Misfolding and Neurodegenerative Diseases

Neuropathological spectrum of synucleinopathies

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α-Synuclein Misfolding and Neurodegenerative Diseases