Phase and Electron Microscopic Observations of Lewy Bodies and Melanin Granules in the Substantia Nigra and Locus Caeruleus in Parkinsonʼs Disease

Duffy, Philip E.; Tennyson, Virginia M.

doi:10.1097/00005072-196507000-00003

Cited by 311 publications

(123 citation statements)

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“…Examination of an area more distal to the LB revealed a lack of dense clusters of vesicles, although sparse vesicles that appear to be of similar size are visible ( Figure 7F). These data are consistent with the earlier EM studies of LBs (Duffy and Tennyson, 1965) and suggest that vesicle accumulations, similar to those we report here in our yeast model system, may be important in the initial formation of LBs and the pathogenesis of PD.…”

Section: Evidence Of Vesicular Accumulations In Human Lbssupporting

confidence: 93%

α-Synuclein–induced Aggregation of Cytoplasmic Vesicles inSaccharomyces cerevisiae

Soper¹,

Roy²,

Stieber³

et al. 2008

MBoC

146

168

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Aggregated ␣-synuclein (␣-syn) fibrils form Lewy bodies (LBs), the signature lesions of Parkinson's disease (PD) and related synucleinopathies, but the pathogenesis and neurodegenerative effects of LBs remain enigmatic. Recent studies have shown that when overexpressed in Saccharomyces cerevisiae, ␣-syn localizes to plasma membranes and forms cytoplasmic accumulations similar to human ␣-syn inclusions. However, the exact nature, composition, temporal evolution, and underlying mechanisms of yeast ␣-syn accumulations and their relevance to human synucleinopathies are unknown. Here we provide ultrastructural evidence that ␣-syn accumulations are not comprised of LB-like fibrils, but are associated with clusters of vesicles. Live-cell imaging showed ␣-syn initially localized to the plasma membrane and subsequently formed accumulations in association with vesicles. Imaging of truncated and mutant forms of ␣-syn revealed the molecular determinants and vesicular trafficking pathways underlying this pathological process. Because vesicular clustering is also found in LB-containing neurons of PD brains, ␣-syn-mediated vesicular accumulation in yeast represents a model system to study specific aspects of neurodegeneration in PD and related synucleinopathies. INTRODUCTIONParkinson's disease (PD) is the most prevalent neurodegenerative movement disorder and is characterized by bradykinesia, rigidity, postural instability, and resting tremor (Galvin et al., 2001;Forman et al., 2005), as well as by the loss of dopaminergic neurons and presence of neuronal inclusions, known as Lewy bodies (LBs) and Lewy neurites (Forman et al., 2005). The identification of an ␣-syn gene (SNCA) mutation associated with autosomal dominant PD (Polymeropoulos et al., 1997), and the identification of fibrillar ␣-syn as the principal component of LB pathology (Spillantini et al., 1997), indicate that the LBs formed by ␣-syn define classic PD and are implicated in disease pathogenesis. The subsequent identification of additional disease-linked SNCA mutations (Polymeropoulos et al., 1997;Kruger et al., 1998;Zarranz et al., 2004), as well as replications of the SNCA gene (Singleton et al., 2003;Chartier-Harlin et al., 2004), indicate that both mutant ␣-syn and increased expression of wildtype (WT) ␣-syn can cause neurodegeneration.In addition to PD, filamentous ␣-syn inclusions have been detected in other neurodegenerative diseases including the LB variant of Alzheimer's disease, dementia with LBs, neurodegeneration with brain iron accumulation type-1, and multiple system atrophy, which are collectively known as synucleinopathies (Spillantini et al., 1997;Duda et al., 2000). ␣-syn fibrils exhibit properties of amyloid (Spillantini et al., 1998), and ␣-syn assembles into amyloid fibrils in vitro (Han et al., 1995;Giasson et al., 1999), whereas SNCA mutations can accelerate ␣-syn fibrillization (Conway et al., 1998;Greenbaum et al., 2005). Therefore, it is plausible that ␣-syn misfolds and aggregates into amyloid fibrils that are neurotoxic and play a cau...

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Section: Evidence Of Vesicular Accumulations In Human Lbssupporting

confidence: 93%

α-Synuclein–induced Aggregation of Cytoplasmic Vesicles inSaccharomyces cerevisiae

Soper¹,

Roy²,

Stieber³

et al. 2008

MBoC

146

168

View full text Add to dashboard Cite

show abstract

“…2). The Lewy bodies observed in the enteric nerve plexuses completely coincide in structure and staining reaction with those seen in the central nervous system (GREENFIELD and BOSANQUET, 1953;DUFFY and TENNYSON, 1965).…”

Section: Lewy Bodies In the Enteric Nervous Systemmentioning

confidence: 69%

Lewy bodies in the enteric nervous system in Parkinson's disease.

Wakabayashi

Takahashi

Takeda

et al. 1989

Arch. Histol. Cytol.

126

121

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“…In AD, the most prevalent age-related neurodegenerative disorder, two proteins aggregate to form amyloid fibrils, namely the amyloid-beta peptide (Aβ) and hyperphosphorylated tau protein [14,19]. In PD, α-synuclein (αS) is found to be the main protein in amyloid fibrils present in Lewy's body deposits [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Hemin as a generic and potent protein misfolding inhibitor

Carver

et al. 2014

Biochemical and Biophysical Research Communications

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After the embargo period via non-commercial hosting platforms such as their institutional repository  via commercial sites with which Elsevier has an agreement In all cases accepted manuscripts should: link to the formal publication via its DOI  bear a CC-BY-NC-ND license -this is easy to do, click here to find out how  if aggregated with other manuscripts, for example in a repository or other site, be shared in alignment with our hosting policy  not be added to or enhanced in any way to appear more like, or to substitute for, the published journal article AbstractProtein misfolding causes serious biological malfunction, resulting in diseases including Alzheimer's disease, Parkinson's disease and cataract. Molecules which inhibit protein misfolding are a promising avenue to explore as therapeutics for the treatment of these diseases. In the present study, thioflavin T fluorescence and transmission electron microscopy experiments demonstrated that hemin prevents amyloid fibril formation of kappa-casein, amyloid beta peptide, and α-synuclein by blocking β-sheet structure assembly which is essential in fibril aggregation. Further, inhibition of fibril formation by hemin significantly reduces the cytotoxicity caused by fibrillar amyloid beta peptide in vitro. Interestingly, hemin degrades partially formed amyloid fibrils and prevents further aggregation to mature fibrils. Light scattering assay results revealed that hemin also prevents protein amorphous aggregation of alcohol dehydrogenase, catalase and γs-crystallin. In summary, hemin is a potent agent which generically stabilises proteins against aggregation, and has potential as a key molecule for the development of therapeutics for protein misfolding diseases. Highlights Hemin prevents Aβ42, α-synuclein, and RCM-κ-casein forming amyloid fibrils  Hemin inhibits the β-sheet structure formation of Aβ42  Hemin reduces the cell toxicity caused by fibrillar Aβ42  Hemin dissociates partially formed Aβ42 fibrils  Hemin prevents amorphous aggregation by ADH, catalase and γs-crystallin

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Phase and Electron Microscopic Observations of Lewy Bodies and Melanin Granules in the Substantia Nigra and Locus Caeruleus in Parkinsonʼs Disease

Cited by 311 publications

References 0 publications

α-Synuclein–induced Aggregation of Cytoplasmic Vesicles inSaccharomyces cerevisiae

α-Synuclein–induced Aggregation of Cytoplasmic Vesicles inSaccharomyces cerevisiae

Lewy bodies in the enteric nervous system in Parkinson's disease.

Hemin as a generic and potent protein misfolding inhibitor

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