Crosslinking of α-synuclein by advanced glycation endproducts — an early pathophysiological step in Lewy body formation?

Münch, Gerald; Lüth, Hans-Joachim; Wong, Amanda; Arendt, Th.; Hirsch, Étienne C.; Ravid, Rivka; Riederer, Peter

doi:10.1016/s0891-0618(00)00096-x

Cited by 212 publications

(150 citation statements)

References 25 publications

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“…The incremental aggregation process of ␣-synuclein involves several modifications (misfolding, dimer and oligomer formation, and self-aggregation) and is linked to Parkinson's disease-associated mutations (5,22,(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50). In this study, we detected abnormal ␣-synuclein species based on their detergent solubility and electrophoretic mobility characteristics in three different systems: human DLB cortex, transgenic mice overexpressing wild type human ␣-synuclein, and a transiently transfected cell culture system.…”

Section: Discussionmentioning

confidence: 94%

Hsp70 Reduces α-Synuclein Aggregation and Toxicity

Klucken

Shin

Masliah

et al. 2004

Journal of Biological Chemistry

479

400

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Aggregation and cytotoxicity of misfolded ␣-synuclein is postulated to be crucial in the disease process of neurodegenerative disorders such as Parkinson's disease and DLB (dementia with Lewy bodies). In this study, we detected misfolded and aggregated ␣-synuclein in a Triton X-100 insoluble fraction as well as a high molecular weight product by gel electrophoresis of temporal neocortex from DLB patients but not from controls. We also found similar Triton X-100 insoluble forms of ␣-synuclein in an ␣-synuclein transgenic mouse model and in an in vitro model of ␣-synuclein aggregation. Introducing the molecular chaperone Hsp70 into the in vivo model by breeding ␣-synuclein transgenic mice with Hsp70-overexpressing mice led to a significant reduction in both the high molecular weight and detergent-insoluble ␣-synuclein species. Concomitantly, we found that Hsp70 overexpression in vitro similarly reduced detergent-insoluble ␣-synuclein species and protected cells from ␣-synuclein-induced cellular toxicity. Taken together, these data demonstrate that the molecular chaperone Hsp70 can reduce the amount of misfolded, aggregated ␣-synuclein species in vivo and in vitro and protect it from ␣-synuclein-dependent toxicity.␣-Synuclein is a natively unfolded molecule that can selfaggregate to form oligomers and fibrillar intermediates (1-5) that accumulate to form Lewy bodies (LBs) 1 and Lewy neurites in neurons at risk for degeneration in Parkinson's disease and dementia with Lewy bodies (DLB) (6 -14). For the most part, these ␣-synuclein aggregates are densely compact and can be immunostained for multiple additional components including ubiquitin, synphilin-1, and heat shock proteins (HSPs), which suggests that protein misfolding or degradation is altered in cells that develop LBs. Mouse models of ␣-synuclein aggregation exist that mimic the findings in human brains and show intracellular ␣-synuclein aggregates (15-17). Aggregated ␣-synuclein molecules are less detergent-soluble, and these detergent-insoluble species of ␣-synuclein can be detected in human brain, transgenic mouse models, and in vitro models (18 -21). Although it is known that the conformation of ␣-synuclein in LBs is significantly different from that in the neuropil (22), it is unclear which conformation of ␣-synuclein contributes to inclusion formation. In addition to the formation of intracellular aggregates, ␣-synuclein is also cytotoxic. It has been postulated that ␣-synuclein oligomers found in Parkinson's disease tissue by Western blot analysis represent the toxic species (5).HSPs belong to the family of chaperone proteins and are important in both refolding misfolded proteins and directing proteins toward proteasomal degradation (23-25). HSPs can be protective in several neurodegeneration models (26 -29), and recent data in the fly model suggest that overexpression of the molecular chaperone Hsp70 protects against ␣-synuclein-induced degeneration (26, 30). Hsp70 and its related co-chaperones may be important in ␣-synuclein misfolding. In fact, sever...

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Section: Discussionmentioning

confidence: 94%

Hsp70 Reduces α-Synuclein Aggregation and Toxicity

Klucken

Shin

Masliah

et al. 2004

Journal of Biological Chemistry

479

400

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“…Advanced glycation endproducts (AGEP) and iron interact with AS aggregation [114,115], which is further promoted by increased calcium [116]. Hsp90 modulates assembly of AS in an ATP-dependent manner by restricting conformational fluctuations [117].…”

Section: The Synuclein Protein Familymentioning

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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“…Furthermore, AGE accumulation has been observed in incidental Lewy Body diseases (a presymptomatic PD state) as well as in the Lewy bodies of PD patients [73]. These studies suggest AGEs/RAGE binding plays an important role during the early stages of neurodegenerative diseases [73].…”

Section: High Mobility Group Box 1 Protein (Hmgb1)mentioning

confidence: 88%

“…In the human AD brain, AGEs are distributed in neuron cytoplasm in the hippocampus and para-hippocampal gyrus and in one study, serum and CSF levels of AGEs were suggested as biomarkers for the early detection of AD [72]. Furthermore, AGE accumulation has been observed in incidental Lewy Body diseases (a presymptomatic PD state) as well as in the Lewy bodies of PD patients [73]. These studies suggest AGEs/RAGE binding plays an important role during the early stages of neurodegenerative diseases [73].…”

Section: High Mobility Group Box 1 Protein (Hmgb1)mentioning

confidence: 97%