Inhibition of fibril formation and toxicity of a fragment of α-synuclein by an N-methylated peptide analogue

Bodles, Angela M.; El-Agnaf, Omar M. A.; Greer, Brett; Guthrie, David J. S.; Irvine, G. Brent

doi:10.1016/j.neulet.2003.12.077

Cited by 57 publications

(48 citation statements)

References 15 publications

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“…Indeed, various peptides/proteins that inhibit protein aggregation have been reported to exert therapeutic effects in cell culture and animal models of these diseases [46,47]. Furthermore, the recent study by Carrion-Vazquez and colleagues [27] suggests that QBP1 may, in fact, have potential as a therapy also for at least some of these other protein misfolding diseases, such as PD.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Misfolding/Aggregation Using Polyglutamine Binding Peptide QBP1 as a Therapy for the Polyglutamine Diseases

et al. 2013

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Protein misfolding and aggregation in the brain have been recognized to be crucial in the pathogenesis of various neurodegenerative diseases, including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases, which are collectively called the "protein misfolding diseases". In the polyQ diseases, an abnormally expanded polyQ stretch in the responsible proteins causes the proteins to misfold and aggregate, eventually resulting in neurodegeneration. Hypothesizing that polyQ protein misfolding and aggregation could be inhibited by molecules specifically binding to the expanded polyQ stretch, we identified polyQ binding peptide 1 (QBP1). We show that QBP1 does, indeed, inhibit misfolding and aggregation of the expanded polyQ protein in vitro. Furthermore overexpression of QBP1 by the crossing of transgenic animals inhibits neurodegeneration in Drosophila models of the polyQ diseases. We also introduce our attempts to deliver QBP1 into the brain by administration using viral vectors and protein transduction domains. Interestingly, recent data suggest that QBP1 can also inhibit the misfolding/aggregation of proteins responsible for other protein misfolding diseases, highlighting the potential of QBP1 as a general therapeutic molecule for a wide range of neurodegenerative diseases. We hope that in the near future, aggregation inhibitor-based drugs will be developed and bring relief to patients suffering from these currently intractable protein misfolding diseases.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Misfolding/Aggregation Using Polyglutamine Binding Peptide QBP1 as a Therapy for the Polyglutamine Diseases

et al. 2013

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“…Their mode of action seems to be insertion into the newly forming protein assemblies, which are held together by interactions between β-strands in an incipient β-sheet, preventing additional β-strands from being added. Several peptides derived from the central hydrophobic region (residues 68-72) of α-synuclein have been shown to prevent aggregation of the full-length protein (150). A cell-permeable version of one of these inhibitors was able to reduce toxicity in cells transfected with mutant A53T α-synuclein (151).…”

Section: P R O T E I N a G G R E G A T I O N I N N E U R O D E G E N mentioning

confidence: 99%

Protein Aggregation in the Brain: The Molecular Basis for Alzheimer’s and Parkinson’s Diseases

Irvine

El‐Agnaf

Shankar

et al. 2008

Mol Med

459

349

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“…Because ␣-syn self-associates to form oligomers and fibrils, the first treatment strategies for synucleinopathies such as Parkinson disease attempted to disrupt self-association (31, 32) (e.g. by using peptide inhibitors derived from the ␣-syn sequence) (33,34). However, the formation of neuronal ␣-syn inclusions in an MSA mouse model is also facilitated by ␣-syn⅐␤-III tubulin binding (12), necessitating an alternative strategy.…”

Section: Discussionmentioning

confidence: 99%

β-III Tubulin Fragments Inhibit α-Synuclein Accumulation in Models of Multiple System Atrophy

Suzuki

Jin

Iwase

et al. 2014

Journal of Biological Chemistry

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Background: Neuronal and oligodendrocytic aggregation of insoluble ␣-synuclein contributes to neuropathology in multiple system atrophy. Results: ␣-Synuclein binds directly to ␤-III tubulin. A fragment carrying the ␣-synuclein-binding site inhibited ␣-synuclein⅐␤-III tubulin complex formation and intracellular ␣-synuclein accumulation. Conclusion: Inhibition of ␣-synuclein binding to ␤-III tubulin may be an effective strategy for preventing ␣-synuclein accumulation. Significance: Small ␤-III tubulin fragments may inhibit neurodegeneration in multiple system atrophy.

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Inhibition of fibril formation and toxicity of a fragment of α-synuclein by an N-methylated peptide analogue

Cited by 57 publications

References 15 publications

Inhibition of Protein Misfolding/Aggregation Using Polyglutamine Binding Peptide QBP1 as a Therapy for the Polyglutamine Diseases

Inhibition of Protein Misfolding/Aggregation Using Polyglutamine Binding Peptide QBP1 as a Therapy for the Polyglutamine Diseases

Protein Aggregation in the Brain: The Molecular Basis for Alzheimer’s and Parkinson’s Diseases

β-III Tubulin Fragments Inhibit α-Synuclein Accumulation in Models of Multiple System Atrophy

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