Characterizing the inhibition of α‐synuclein oligomerization by a pharmacological chaperone that prevents prion formation by the protein PrP

Dong, Chun‐Hua; Garen, Craig R.; Mercier, Pascal; Petersen, Nils O.; Woodside, Michael T.

doi:10.1002/pro.3684

Cited by 10 publications

(7 citation statements)

References 88 publications

(150 reference statements)

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“…Natural chemical chaperones, including myo -inositol, are typically expected to stabilize the native state of a protein, either directly by binding it or indirectly by destabilizing the unfolded state ( Beg et al, 2017 ; Clark et al, 2012 ; Dandage et al, 2015 ; Dong et al, 2019 ; Gault et al, 2018 ; Gupta et al, 2016 ; Morgan et al, 2019 ; Okiyoneda et al, 2013 ; Street et al, 2006 ). In some cases, osmolytes have been found to alter aggregate morphology ( Bashir et al, 2020 ; Marasini et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

A native chemical chaperone in the human eye lens

Serebryany

Chowdhury

Woods

et al. 2022

eLife

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Cataract is one of the most prevalent protein aggregation disorders and still the most common cause of vision loss worldwide. The metabolically quiescent core region of the human lens lacks cellular or protein turnover; it has therefore evolved remarkable mechanisms to resist light-scattering protein aggregation for a lifetime. We now report that one such mechanism involves an unusually abundant lens metabolite, myo-inositol, suppressing aggregation of lens crystallins. We quantified aggregation suppression using our previously well-characterized in vitro aggregation assays of oxidation-mimicking human γD-crystallin variants and investigated myo-inositol's molecular mechanism of action using solution NMR, negative-stain TEM, differential scanning fluorometry, thermal scanning Raman spectroscopy, turbidimetry in redox buffers, and free thiol quantitation. Unlike many known chemical chaperones, myo-inositol's primary target was not the native, unfolded, or final aggregated states of the protein; rather, we propose that it was the rate-limiting bimolecular step on the aggregation pathway. Given recent metabolomic evidence that it is severely depleted in human cataractous lenses compared to age-matched controls, we suggest that maintaining or restoring healthy levels of myo-inositol in the lens may be a simple, safe, and globally accessible strategy to prevent or delay lens opacification due to age-onset cataract.

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Section: Discussionmentioning

confidence: 99%

A native chemical chaperone in the human eye lens

Serebryany

Chowdhury

Woods

et al. 2022

eLife

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show abstract

“…Natural chemical chaperones, including myo-inositol, are typically expected to stabilize the native state of a protein, either directly by binding it or indirectly by destabilizing the unfolded state. [46][47][48][55][56][57][58][59][60] In some cases, osmolytes have been found to alter aggregate morphology. 61,62 Inhibitors of aggregation kinetics whose primary target is transient oligomeric states or nuclei have been more challenging to find, let alone characterize, but they are of especially high interest as possible treatments for proteinopathies.…”

Section: Discussionmentioning

confidence: 99%

A native chemical chaperone in the human eye lens

Serebryany

Chowdhury

McClelland

et al. 2020

Preprint

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Cataract is one of the most prevalent protein aggregation disorders and still the most common cause of vision loss worldwide. The metabolically quiescent core region of the human lens lacks cellular or protein turnover; it has therefore evolved remarkable mechanisms to resist light-scattering protein aggregation for a lifetime. We now report that one such mechanism involves an unusually abundant lens metabolite, myo-inositol, suppressing aggregation of lens crystallins. We quantified aggregation suppression using our previously well-characterized in vitro aggregation assays of oxidation-mimicking human γD-crystallin variants and investigated myo-inositol's molecular mechanism of action using solution NMR, negative-stain TEM, differential scanning fluorometry, thermal scanning Raman spectroscopy, turbidimetry in redox buffers, and free thiol quantitation. Unlike many known chemical chaperones, myo-inositol's primary target was neither the native nor the unfolded state of the protein, nor the final aggregated state, but rather the rate-limiting bimolecular step on the aggregation pathway. Given recent metabolomic evidence that it is severely depleted in human cataractous lenses compared to age-matched controls, we suggest that maintaining or restoring healthy levels of myo-inositol in the lens may be a simple, safe, and globally accessible strategy to prevent or delay lens opacification due to age-onset cataract.

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“…Titrations of ligand into buffer were measured and used for background subtraction before fitting the data. A one set of sites binding model was used for all experiments and binding curves were fit with a Gaussian nonlinear regression model on Prism 9.4 (GraphPad Software) [ 49 – 51 ]. Data at each step of analysis is provided in supplementary figures (Supp.…”

Section: Methodsmentioning

confidence: 99%

Polymorphic Alpha-Synuclein Oligomers: Characterization and Differential Detection with Novel Corresponding Antibodies

et al. 2023

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The pathological hallmark of many neurodegenerative diseases is the accumulation of characteristic proteinaceous aggregates. Parkinson’s disease and dementia with Lewy bodies can be characterized as synucleinopathies due to the abnormal accumulation of the protein alpha-synuclein (α-Syn). Studies have shown amyloidogenic proteins such as α-Syn and tau can exist as polymorphic aggregates, a theory widely studied mostly in their fibrillar morphology. It is now well understood that an intermediate state of aggregates, oligomers, are the most toxic species. We have shown α-Syn, when modified by different physiological inducers, result in distinct oligomeric conformations of α-Syn. Polymorphic α-Syn oligomers exhibit distinct properties such as aggregate size, conformation, and differentially interact with tau. In this study, we confirm α-Syn oligomeric polymorphs furthermore using in-house novel α-Syn toxic conformation monoclonal antibodies (SynTCs). It is unclear the biological relevance of α-Syn oligomeric polymorphisms. Utilizing a combination of biochemical, biophysical, and cell-based assays, we characterize α-Syn oligomeric polymorphs. We found α-Syn oligomeric polymorphs exhibit distinct immunoreactivity and SynTCs exhibit differential selectivity and binding affinity for α-Syn species. Isothermal titration calorimetry experiments suggest distinct α-Syn:SynTC binding enthalpies in a species-specific manner. Additionally, we found SynTCs differentially reduce α-Syn oligomeric polymorph-mediated neurotoxicity and propagation in primary cortical neurons in a polymorph-specific manner. These studies demonstrate the biological significance of polymorphic α-Syn oligomers along with the importance of polymorph-specific antibodies that target toxic α-Syn aggregates. Monoclonal antibodies that can target the conformational heterogeneity of α-Syn oligomeric species and reduce their mediated toxicity have promising immunotherapeutic potential.

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Characterizing the inhibition of α‐synuclein oligomerization by a pharmacological chaperone that prevents prion formation by the protein PrP

Cited by 10 publications

References 88 publications

A native chemical chaperone in the human eye lens

A native chemical chaperone in the human eye lens

A native chemical chaperone in the human eye lens

Polymorphic Alpha-Synuclein Oligomers: Characterization and Differential Detection with Novel Corresponding Antibodies

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