The Role of α-Synuclein Assembly and Metabolism in the Pathogenesis of Lewy Body Disease

Hashimoto, Makoto; Kawahara, Kohichi; Bar-On, Pazit; Rockenstein, Edward; Crews, Leslie; Masliah, Eliezer

doi:10.1385/jmn:24:3:343

Cited by 46 publications

(37 citation statements)

References 77 publications

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“…Abnormal accumulation is considered to be the result of alterations in the balance between ␣-syn production, aggregation, and clearance (Hashimoto et al, 2004). Although accumulation of ␣-syn in mature neurons might result in synaptic dysfunction and eventually in cell death, in NPCs ␣-syn interferes with neurogenesis, more specifically with the survival of neural progeny in the terminal phase of neuronal differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence indicates that abnormal accumulation of misfolded ␣-syn in the synaptic terminals and axons plays an important role (Iwatsubo et al, 1996;Hashimoto and Masliah, 1999;Lansbury, 1999;Hashimoto et al, 2004;Kramer and Schulz-Schaeffer, 2007). Neurodegeneration in these disorders affects primarily the striatonigral system, but, in cases with cognitive impairment, there is more widespread degeneration including neuronal populations in the striatum, hippocampus, and neocortex (Harding et al, 2002;McKeith et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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α-Synuclein Alters Notch-1 Expression and Neurogenesis in Mouse Embryonic Stem Cells and in the Hippocampus of Transgenic Mice

Crews¹,

Mizuno²,

Desplats³

et al. 2008

J. Neurosci.

121

107

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

α-Synuclein Alters Notch-1 Expression and Neurogenesis in Mouse Embryonic Stem Cells and in the Hippocampus of Transgenic Mice

Crews¹,

Mizuno²,

Desplats³

et al. 2008

J. Neurosci.

121

107

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“…The main constituent of the Lewy bodies is the ␣-synuclein protein (␣-syn) (12,13). ␣-syn is a protein whose dysfunction has been associated with several neurodegenerative diseases in addition to PD (14,15).…”

mentioning

confidence: 99%

A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent α-Synuclein (α-syn) Aggregation Inhibitor

Shaltiel-Karyo¹,

Frenkel-Pinter²,

Rockenstein

et al. 2013

Journal of Biological Chemistry

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Background: ␣-syn aggregation is a main pathology of PD. Results: Mannitol interferes with ␣-syn aggregation in vitro and in vivo, whereas no adverse effects were observed in control animals. Conclusion:In addition to its BBB-disrupting properties, mannitol, a chemical chaperon, may serve as a potential drug. Significance: mannitol may serve as a basis for a dual mechanism therapeutic agent for treating PD.

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“…The extracellularly deposited ␣-synuclein, or the central segment of it, is known as the "non-A␤ component" of amyloid and is involved in the formation of senile plaques in Alzheimer disease (AD). 2 The intraneuronal aggregation of ␣-synuclein leads to the formation of Lewy bodies. These inclusions were initially thought to hallmark the degenerating dopaminergic neurons in Parkinson disease; however, they are abundant in cortical neurons and basal ganglia in distinct neurodegenerative dementias, such as AD and Lewy body dementia (LBD), and are often found in neurons of elderly people without any clinical record of parkinsonism or dementia (1).…”

mentioning

confidence: 99%

“…They may also contain many other components (such as synphilin-1, Dorfin, or Parkin), which have not yet been investigated in detail (see Ref. 2 …”

mentioning

confidence: 99%

Transglutaminase-mediated Intramolecular Cross-linking of Membrane-bound α-Synuclein Promotes Amyloid Formation in Lewy Bodies

Nemes

Petrovski

Aerts

et al. 2009

Journal of Biological Chemistry

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The ␣-synuclein immunopositive and chaotrope-insoluble material from human brains with Lewy body pathology was analyzed by mass spectrometry. From the proteinase K-cleavable peripheral fraction of Lewy bodies, which was densely crosslinked by ␥-glutamyl-⑀-lysine bonds between HspB1 and ubiquitin in a pattern similar to neurofibrillary tangles (Nemes, Z., Devreese, B., Steinert, P. M., Van Beeumen, J., and Fésüs, L. (2004) FASEB J. 18, 1135-1137), 53 proteins were identified. In the core of Lewy bodies only ␣-synuclein was found, and it contained a low amount of intramolecular cross-links between Gln-99 and Lys-58. In vitro cross-linking of ␣-synuclein by transglutaminases 1-3 and 5 produced a heterogeneous population of variably cross-linked ␣-synucleins in solution, which inhibited the aggregation of the protein into amyloid. However, in the presence of phosphatidylserine-rich membranes and micromolar calcium concentrations, the cross-linking by transglutaminases 1, 2, and 5 showed specificity toward the utilization of Gln-99 and Lys-58. As shown by thioflavin T fluorescence monitoring, the formation of this cross-link accelerated the aggregation of native ␣-synuclein. Chemical cross-linking of residues 58 -99 triggered amyloid formation, whereas such bonding of residues 99 to 10 was inhibitory. Our findings reveal the pivotal role of membrane attachment and transglutaminasemediated intermolecular cross-linking for the propagative misfolding and aggregation of ␣-synuclein.

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The Role of α-Synuclein Assembly and Metabolism in the Pathogenesis of Lewy Body Disease

Cited by 46 publications

References 77 publications

α-Synuclein Alters Notch-1 Expression and Neurogenesis in Mouse Embryonic Stem Cells and in the Hippocampus of Transgenic Mice

α-Synuclein Alters Notch-1 Expression and Neurogenesis in Mouse Embryonic Stem Cells and in the Hippocampus of Transgenic Mice

A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent α-Synuclein (α-syn) Aggregation Inhibitor

Transglutaminase-mediated Intramolecular Cross-linking of Membrane-bound α-Synuclein Promotes Amyloid Formation in Lewy Bodies

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