Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form

Collier, Timothy J.; Srivastava, Kinshuk Raj; Justman, Craig J.; Grammatopoulous, Tom; Hutter‐Paier, Birgit; Prokesch, Manuela; Havas, Daniel; Rochet, Jean‐Christophe; Liu, Fang; Jock, Kevin; Oliveira, Patrícia de; Stirtz, Georgia L.; Dettmer, Ulf; Sortwell, Caryl E.; Feany, Mel Β.; Lansbury, Peter T.; Lapidus, Lisa J.; Paumier, Katrina L.

doi:10.1016/j.nbd.2017.07.007

Cited by 32 publications

(25 citation statements)

References 79 publications

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“…Given the complexity of synucleinopathies, multi-therapy that targets multiple proteins at their oligomeric states as well as altered biological pathways might turn out to be superior to monotherapies. Lastly, immunotherapies may be combined with modifiers of intracellular ␣Syn dynamics [232,233] or lipid pathways that affect ␣Syn biology [234][235][236].…”

Section: Multi-therapy With Other Amyloid Proteinsmentioning

confidence: 99%

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Kayed

Dettmer

Lesné

2020

JPD

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There is growing recognition in the field of neurodegenerative diseases that mixed proteinopathies are occurring at greater frequency than originally thought. This is particularly true for three amyloid proteins defining most of these neurological disorders, amyloid-beta (A␤), tau, and alpha-synuclein (␣Syn). The coexistence and often co-localization of aggregated forms of these proteins has led to the emergence of concepts positing molecular interactions and cross-seeding between A␤, tau, and ␣Syn aggregates. Amongst this trio, ␣Syn has received particular attention in this context during recent years due to its ability to modulate A␤ and tau aggregation in vivo, to interact at a molecular level with A␤ and tau in vivo and to cross-seed tau in mice. Here we provide a comprehensive, critical, and accessible review about the expression, role and nature of endogenous soluble ␣Syn oligomers because of recent developments in the understanding of ␣Syn multimerization, misfolding, aggregation, cross-talk, spreading and cross-seeding in neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, and Huntington's disease. We will also discuss our current understanding about the relative toxicity of endogenous ␣Syn oligomers in vivo and in vitro, and introduce potential opportunities to counter their deleterious effects.

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Section: Multi-therapy With Other Amyloid Proteinsmentioning

confidence: 99%

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Kayed

Dettmer

Lesné

2020

JPD

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“…It would be ideal for these clinical efforts to be complemented by well-designed pre-clinical models aiming to understand the causal link between GM and PD. This could lead to the development of novel therapeutic approaches aimed at interfering with α-Syn aggregation and clearance [161][162][163].…”

Section: Controversies and Future Directionsmentioning

confidence: 99%

Parkinson’s disease and the gastrointestinal microbiome

et al. 2019

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Recently, there has been a surge in awareness of the gastrointestinal microbiome (GM) and its role in health and disease. Of particular note is an association between the GM and Parkinson's disease (PD) and the realisation that the GM can act via a complex bidirectional communication between the gut and the brain. Compelling evidence suggests that a shift in GM composition may play an important role in the pathogenesis of PD by facilitating the characteristic ascending neurodegenerative spread of αsynuclein aggregates from the enteric nervous system to the brain. Here, we review evidence linking GM changes with PD, highlighting mechanisms supportive of pathological α-synuclein spread and intestinal inflammation in PD. We summarise existing patterns and correlations seen in clinical studies of the GM in PD, together with the impacts of non-motor symptoms, medications, lifestyle, diet and aging on the GM. Roles of GM modulating therapies, including probiotics and faecal microbiota transplantation are discussed. Encouragingly, alterations in the GM have repeatedly been observed in PD, supporting a biological link and highlighting it as a potential therapeutic target.

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“…While these small molecules have shown interesting results in vitro, the main problem with these therapies remains the inability of these molecules to cross the blood-brain barrier. However, a recent study has emerged showing a known antidepressant, nortriptyline (NOR) ( Table 1) as a possible inhibitor of αS [64]. In vitro studies done by Collier et al show a dose-dependent decrease of aggregation by αS in the presence of NOR.…”

Section: Inhibitors Of αS Amyloidogenesis: What Others Have Discoveredmentioning

confidence: 99%

Pre-structured hydrophobic peptide β-strands: A universal amyloid trap?

Sivanesam¹,

Andersen²

2019

Archives of Biochemistry and Biophysics

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Amyloid fibril formation has long been studied because of the variety of proteins that are capable of adopting this structure despite sharing little sequence homology. This makes amyloid fibrils a challenging focus for inhibition studies because the peptides and proteins that form amyloid fibrils cannot be targeted based on a sequence motif. Most peptide inhibitors that target specific amyloidogenic proteins rely heavily on sequence recognition to ensure that the inhibitory peptide is able to bind its target. This approach is limited to targeting one amyloidogenic protein at a time. However, there is increasing evidence of cross-reactivity between amyloidforming polypeptides. It has therefore become more useful to study the similarities between these proteins that goes beyond their sequence homology. Indeed, the observation that amyloidogenic proteins adopt similar secondary structures along the pathway to fibril formation opens the way to an interesting investigation: the development of inhibitors that could be universal amyloid traps. The review below will analyze two specific amyloidogenic proteins, α-synuclein and human amylin, and introduce a small number of peptides that have been shown to be capable of inhibiting the amyloidogenesis of both of these very dissimilar polypeptides. Some of the inhibitory peptide motifs may indeed, be applicable to Aβ and other amyloidogenic systems.

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Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form

Cited by 32 publications

References 79 publications

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Parkinson’s disease and the gastrointestinal microbiome

Pre-structured hydrophobic peptide β-strands: A universal amyloid trap?

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