The Sherpa hypothesis: Phenotype-Preserving Disordered Proteins stabilize the phenotypes of neurons and oligodendrocytes

Norris, Victor; Oláh, Judit; Krylov, Sergey N.; Uversky, Vladimir N.; Ovádi, Judit

doi:10.1038/s41540-023-00291-8

Cited by 4 publications

(4 citation statements)

References 73 publications

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“…New ideas and new findings in the field of neurodegenerative diseases hold the promise of new diagnostic techniques and therapies. Focusing on synucleinopathies, these ideas include the Sherpa hypothesis which proposes that Phenotype-Preserving Disordered Proteins (PPDPs), such as TPPP and SYN, and oligomeric structures as well as the homoand hetero-associations of these disordered proteins can generate distinct, physiologically/pathologically appropriate phenotypes [106]. SYN and TPPP as PPDPs assist in the maintenance of the phenotypes of neurons and OLGs despite these cells being subject to stresses that might otherwise disrupt their phenotypes [106].…”

Section: Conclusion and Beyondmentioning

confidence: 99%

“…Focusing on synucleinopathies, these ideas include the Sherpa hypothesis which proposes that Phenotype-Preserving Disordered Proteins (PPDPs), such as TPPP and SYN, and oligomeric structures as well as the homoand hetero-associations of these disordered proteins can generate distinct, physiologically/pathologically appropriate phenotypes [106]. SYN and TPPP as PPDPs assist in the maintenance of the phenotypes of neurons and OLGs despite these cells being subject to stresses that might otherwise disrupt their phenotypes [106]. The dynamic microtubule system makes a powerful contribution to the generation of coherent phenotypes by binding certain proteins/enzymes such as SYN and TPPP [106,107].…”

Section: Conclusion and Beyondmentioning

confidence: 99%

“…SYN and TPPP as PPDPs assist in the maintenance of the phenotypes of neurons and OLGs despite these cells being subject to stresses that might otherwise disrupt their phenotypes [106]. The dynamic microtubule system makes a powerful contribution to the generation of coherent phenotypes by binding certain proteins/enzymes such as SYN and TPPP [106,107]. The disturbance of the multiple functions of the microtubule network is particularly important in brain cells, as observed in a variety of neurodegenerative disorders [108,109].…”

Section: Conclusion and Beyondmentioning

confidence: 99%

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Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP

Oláh,

Norris,

Lehotzky

et al. 2024

Cells

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Neurological disorders such as Parkinsonism cause serious socio-economic problems as there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner of SYN, termed Tubulin Polymerization Promoting Protein (TPPP), which has important physiological and pathological activities such as the regulation of the microtubule network and the promotion of SYN aggregation. The role of TPPP in Parkinsonism is often neglected in research, which we here attempt to remedy. In the normal brain, SYN and TPPP are expressed endogenously in neurons and oligodendrocytes, respectively, whilst, at an early stage of Parkinsonism, soluble hetero-associations of these proteins are found in both cell types. The cell-to-cell transmission of these proteins, which is central to disease progression, provides a unique situation for specific drug targeting. Different strategies for intervention and for the discovery of biomarkers include (i) interface targeting of the SYN-TPPP hetero-complex; (ii) proteolytic degradation of SYN and/or TPPP using the PROTAC technology; and (iii) depletion of the proteins by miRNA technology. We also discuss the potential roles of SYN and TPPP in the phenotype stabilization of neurons and oligodendrocytes.

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Section: Conclusion and Beyondmentioning

confidence: 99%

Section: Conclusion and Beyondmentioning

confidence: 99%

Section: Conclusion and Beyondmentioning

confidence: 99%

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Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP

Oláh,

Norris,

Lehotzky

et al. 2024

Cells

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“…17 This example is especially notable since only a small methyl group (-aminoisobutyric acid -AIB) was used to convert a highly aggregating peptide into an aggregation-inhibitor capable of preventing IAPP toxicity by reducing pathological β-sheet formations. 17,21 While molecular foldamers and β-inhibitors show great promise as IDP regulators through their preference for a single secondary structure, alpha helices and β-sheets, respectively), their mechanism of action is still unclear. 17,22 To elucidate their mechanisms, we turn to all-atom molecular dynamics (aa-MD) simulations, which can predict binding affinities of molecules across multiple conformations that are currently inaccessible by experimental methods.…”

Section: Introductionmentioning

confidence: 99%

Drugging Disordered Proteins by Conformational Selection to Inform Therapeutic Intervention

Bogin,

Levine

2024

Preprint

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Drugging intrinsically disordered proteins (IDPs) has historically been a major challenge due to their lack of stable binding sites, conformational heterogeneity, and rapid ability to self-associate or bind non-specific neighbors. Furthermore, it is unclear whether binders of disordered proteins i) induce entirely new conformations or ii) target transient pre-structured conformations via stabilizing existing states. To distinguish between these two mechanisms, we utilize molecular dynamics simulations to induce structured conformations in islet amyloid polypeptide (IAPP), a disordered endocrine peptide implicated in Type II Diabetes. Using umbrella sampling, we measureconformation-specificaffinities of molecules previously shown to bind IAPP to determine if they can discriminate between two distinct IAPP conformations (fixed in either ⍺-helix or β-sheet). We show our two-state model of IAPP faithfully predicts the experimentally observed selectivity of two classes of IAPP binders while revealing differences in their molecular mechanisms of binding. Specifically, the binding preferences of foldamers designed for human IAPP was not fully accounted for by conformational selection, unlike β-breaking peptides designed to mimic IAPP self-assembly sequences. Furthermore, the binding of these foldamers, but not β-breaking peptides, was disrupted by changes in the rat IAPP sequence. Taken together, our data quantifies the sequence and conformational specificity for IAPP binders and reveals conformational selection sometimes overrides sequence-level specificity. This work highlights the important role of conformational selection in stabilizing IDPs, and it reveals how fixed conformations can provide a tractable target for developing disordered protein binders.

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Structural insights into the disulfide isomerase and chaperone activity of TrbB of the F plasmid type IV secretion system

Apostol,

Bragagnolo,

Rodriguez

et al. 2024

Current Research in Structural Biology

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The Sherpa hypothesis: Phenotype-Preserving Disordered Proteins stabilize the phenotypes of neurons and oligodendrocytes

Cited by 4 publications

References 73 publications

Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP

Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP

Drugging Disordered Proteins by Conformational Selection to Inform Therapeutic Intervention

Structural insights into the disulfide isomerase and chaperone activity of TrbB of the F plasmid type IV secretion system

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