Three‐Layered Structure Shared Between Lewy Bodies and Lewy Neurites—Three‐Dimensional Reconstruction of Triple‐Labeled Sections

Kanazawa, Tohru; Uchihara, Toshiki; Takahashi, Atsushi; Nakamura, Ayako; Orimo, Satoshi; Mizusawa, Hidehiro

doi:10.1111/j.1750-3639.2008.00140.x

Cited by 55 publications

(57 citation statements)

References 44 publications

(70 reference statements)

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“…'Pale bodies', rounded areas of granular, pale-staining eosinophilic material displacing neuromelanin in brainstem neurons, are considered precursors of LBs [21]. LBs are associated with coarse, dystrophic ''Lewy neurites'' which may evolve into LBs [51]. All these Lewy structures share immunocytochemical and biochemical characteristics, the major components being aggregated aSyn, ubiquitin (Ub), phosphorylated neurofilaments, PARKIN, components of the ubiquitinproteasome system, molecular chaperons, and lipids (see [41,45,91]).…”

Section: Formation Of Lewy Bodiesmentioning

confidence: 99%

Formation and development of Lewy pathology: a critical update

Jellinger¹

2009

J Neurol

171

141

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Filamentous protein inclusions in neurons (Lewy bodies, LB) and dystrophic neurites containing pathologic alpha-synuclein (alpha Syn) are the morphologic hallmarks of sporadic Parkinson disease (PD) and dementia with Lewy bodies (DLB), but are also found in aged subjects and in a variety of neurogenerative disorders. They occur in the central, peripheral, and autonomic nervous system as an essential or coincident feature. Their formation runs through several phases from initial dust-like particles cross-linked with alpha Syn to aggregation of ubiquitinated dense filaments, formation of LBs, finally degradation and death of the afflicted neurons. Pathologic accumulation of alpha Syn/LBs proposed by Braak et al. (Neurobiol Aging 24:197-211, 2003), following a predictable sequence of lesions in six stages with ascending progression from medullary and olfactory nuclei to the cortex, has been considered to be linked to clinical dysfunctions. The consensus pathologic guidelines of DLB (Neurology 65:1863-1872, 2005), by semiquantitative scoring to alpha Syn pathology (LB density and distribution) in specific brain regions, distinguish three phenotypes (brainstem, transitional/limbic, and diffuse neocortical), and also consider concomitant Alzheimer-related pathology. alpha Syn pathology in the amygdala is often associated with Alzheimer disease. Although some retrospective clinico-pathologic studies have largely confirmed the Braak LB staging system, it shows neither correlation to the clinical severity and duration of parkinsonism nor to nigral alpha Syn burden and cell loss which significantly correlates with resulting striatal loss of dopamine, dopamine transporter and tyrosine hydroxylase, duration and severity of motor dysfunction. Between 6.3 and 43% of clinically manifested PD cases did not follow this pattern, and in 7-8.3% of those with alpha Syn-positive inclusions in midbrain and cortex the medullary nuclei were spared. On the other hand, 30-55% of elderly subjects with widespread Lewy pathology revealed no neuropsychiatric symptoms or were not classifiable. Therefore, detection and staging of Lewy pathology without assessment of neuronal loss in specific areas may not have clinical impact and its predictive validity is questionable. For demented patients, modified criteria for categorization of Lewy pathology were proposed. If robust correlations between clinical course and Lewy/alpha Syn pathology are to be confirmed by future studies, the currently used morphologic staging/classification systems should be revised accordingly.

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Section: Formation Of Lewy Bodiesmentioning

confidence: 99%

Formation and development of Lewy pathology: a critical update

Jellinger¹

2009

J Neurol

171

141

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“…LBs are accompanied by dystrophic neurites, which according to recent 3-dimensional studies may evolve into LBs, with Ub at the core and neurofilaments at the outermost layer [655]. LB pathology [340,429,[663][664][665].…”

Section: Formation and Development Of As/lewy Pathologymentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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“…However, these inclusions have distinctly different morphologies, with LBs being largely spherical whilst LNs have rod-or snake-like morphologies (Braak et al, 1999). Work by Kanazawa et al, using 3D reconstruction of confocal images revealed that both LB and LN share the same structural components of an inner filamentous α-syn and ubiquitin layer coated by neurofilament (Kanazawa et al, 2008), also finding LB/LN intermediary like structures sharing the same characteristics. This suggests LNs may be an earlier LB stage, thus explaining the abundance of these inclusions together in affected brain regions.…”

Section: Alpha-synuclein In Diseasementioning

confidence: 96%

Potential Modes of Intercellular Alpha-Synuclein Transmission

Valdinocci

Radford

Siow

et al. 2017

Preprint

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Intracellular aggregates of the alpha-synuclein protein result in cell loss and dysfunction in Parkinson's disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as alpha-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby alpha-synuclein aggregates mediate cytotoxicity also remain to be fully elucidated. However, recent studies have implicated the cell-to-cell spread of alpha-synuclein as the major mode of disease propagation between brain regions during disease progression. Here, we review the current evidence for different modes of alpha-synuclein cellular release, movement and uptake, including exocytosis, exosomes, tunneling nanotubes, glymphatic flow and endocytosis. A more detailed understanding of the major modes by which alpha-synuclein pathology spreads throughout the brain may provide new targets for therapies that halt the progression of disease.

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Three‐Layered Structure Shared Between Lewy Bodies and Lewy Neurites—Three‐Dimensional Reconstruction of Triple‐Labeled Sections

Cited by 55 publications

References 44 publications

Formation and development of Lewy pathology: a critical update

Formation and development of Lewy pathology: a critical update

The role of α-synuclein in neurodegeneration — An update

Potential Modes of Intercellular Alpha-Synuclein Transmission

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