Multifaceted interactions mediated by intrinsically disordered regions play key roles in alpha synuclein aggregation

Khare, Sagar D.; Chinchilla, Priscilla; Baum, Jean

doi:10.1016/j.sbi.2023.102579

Cited by 17 publications

(8 citation statements)

References 53 publications

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“… 45 In vitro , this pH disrupts electrostatic interactions within the fuzzy coat surrounding α-syn fibrils, exposing their β-sheet core, and favoring interaction of the monomer with the fibril surface. 46 Furthermore, this pH is biologically relevant as it mimics that of lysosomes, which are important in PD. 47 Under these conditions, αSP1 showed a clear inhibitory effect on α-syn amyloid formation at substoichiometric concentrations of αSP1 to α-syn as low as 1:20 ( Figure 3 D), consistent with aSP1 inhibiting secondary nucleation processes.…”

Section: Results and Discussionmentioning

confidence: 99%

A Potent Sybody Selectively Inhibits α-Synuclein Amyloid Formation by Binding to the P1 Region

Gialama,

Vadukul,

Thrush

et al. 2024

J. Med. Chem.

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Increasing research efforts focus on exploiting antibodies to inhibit the amyloid formation of neurodegenerative proteins. Nevertheless, it is challenging to discover antibodies that inhibit this process in a specific manner. Using ribosome display, we screened for synthetic single-domain antibodies, i.e., sybodies, of the P1 region of α-synuclein (residues 36−42), a protein that forms amyloid in Parkinson's disease and multiple-system atrophy. Hits were assessed for direct binding to a P1 peptide and the inhibition of amyloid formation. We discovered a sybody, named αSP1, that inhibits amyloid formation of α-synuclein at substoichiometric concentrations in a specific manner, even within highly crowded heterogeneous mixtures. Fluorescence resonance energy transfer-based binding assays and seeding experiments with and without αSP1 further demonstrate the importance of the P1 region for both primary and secondary nucleation mechanisms of amyloid assembly.

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Section: Results and Discussionmentioning

confidence: 99%

A Potent Sybody Selectively Inhibits α-Synuclein Amyloid Formation by Binding to the P1 Region

Gialama,

Vadukul,

Thrush

et al. 2024

J. Med. Chem.

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“…The predominance of acidic residues leads to an upshift of the p K a values and charge regulation upon fibril formation . Moreover, the intra- and intermolecular interactions, in particular between the oppositely charged termini, seem to be important in α-synuclein self-assembly, as studied using NMR spectroscopy, native mass spectrometry, and MD simulations − and recently reviewed …”

Section: α-Synuclein Structurementioning

confidence: 99%

“… 22 Moreover, the intra- and intermolecular interactions, in particular between the oppositely charged termini, seem to be important in α-synuclein self-assembly, as studied using NMR spectroscopy, native mass spectrometry, and MD simulations 23 − 27 and recently reviewed. 28 …”

Section: α-Synuclein Structurementioning

confidence: 99%

Interplay of α-synuclein with Lipid Membranes: Cooperative Adsorption, Membrane Remodeling and Coaggregation

Makasewicz,

Linse,

Sparr

2024

JACS Au

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α-Synuclein is a small neuronal protein enriched at presynaptic termini. It is hypothesized to play a role in neurotransmitter release and synaptic vesicle cycling, while the formation of α-synuclein amyloid fibrils is associated with several neurodegenerative diseases, most notably Parkinson’s Disease. The molecular mechanisms of both the physiological and pathological functions of α-synuclein remain to be fully understood, but in both cases, interactions with membranes play an important role. In this Perspective, we discuss several aspects of α-synuclein interactions with lipid membranes including cooperative adsorption, membrane remodeling and α-synuclein amyloid fibril formation in the presence of lipid membranes. We highlight the coupling between the different phenomena and their interplay in the context of physiological and pathological functions of α-synuclein.

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“…Alpha-synuclein (α-Syn) is an intrinsically disordered protein [185] that is abundant in the central nervous system [186] and transforms into cross-β-sheets rich amyloid by self-assembly under physiological conditions via partially folded intermediates and soluble oligomers [187]. Some aggregated species of α-Syn formed along the fibrillation are highly toxic and capable of interfering with the functions of different organelles such as mitochondria, endoplasmic reticulum, and plasma membrane [188][189][190].…”

Section: Natural Products Inhibit Degrade and Remodel α-Syn Fibrils T...mentioning

confidence: 99%

Targeting Protein Aggregates with Natural Products: An Optional Strategy for Neurodegenerative Diseases

Xiang

Wang

Liu

et al. 2023

IJMS

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Protein aggregation is one of the hallmarks of aging and aging-related diseases, especially for the neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS), and others. In these diseases, many pathogenic proteins, such as amyloid-β, tau, α-Syn, Htt, and FUS, form aggregates that disrupt the normal physiological function of cells and lead to associated neuronal lesions. Protein aggregates in NDs are widely recognized as one of the important targets for the treatment of these diseases. Natural products, with their diverse biological activities and rich medical history, represent a great treasure trove for the development of therapeutic strategies to combat disease. A number of in vitro and in vivo studies have shown that natural products, by virtue of their complex molecular scaffolds that specifically bind to pathogenic proteins and their aggregates, can inhibit the formation of aggregates, disrupt the structure of aggregates and destabilize them, thereby alleviating conditions associated with NDs. Here, we systematically reviewed studies using natural products to improve disease-related symptoms by reducing or inhibiting the formation of five pathogenic protein aggregates associated with NDs. This information should provide valuable insights into new directions and ideas for the treatment of neurodegenerative diseases.

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Multifaceted interactions mediated by intrinsically disordered regions play key roles in alpha synuclein aggregation

Cited by 17 publications

References 53 publications

A Potent Sybody Selectively Inhibits α-Synuclein Amyloid Formation by Binding to the P1 Region

A Potent Sybody Selectively Inhibits α-Synuclein Amyloid Formation by Binding to the P1 Region

Interplay of α-synuclein with Lipid Membranes: Cooperative Adsorption, Membrane Remodeling and Coaggregation

Targeting Protein Aggregates with Natural Products: An Optional Strategy for Neurodegenerative Diseases

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