Small Molecules Attenuate the Interplay between Conformational Fluctuations, Early Oligomerization and Amyloidosis of Alpha Synuclein

Ghosh, Sumanta Kumar; Kundu, Amrita; Chattopadhyay, Krishnananda

doi:10.1038/s41598-018-23718-3

Cited by 28 publications

(28 citation statements)

References 52 publications

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“…5 a, c). In addition, we found that both substances lead to a significant decrease ( P = 0.012 for anle138b and P = 0.009 for EGCG) in the amount of monomers incorporated per amplification cycle 40 , 41 when compared to the control (Fig. 5 b, d).…”

Section: Resultsmentioning

confidence: 74%

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Dominguez-Meijide

Vasili²,

König³

et al. 2020

Sci Rep

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Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative disorders of the elderly and, therefore, affect a growing number of patients worldwide. Both diseases share, as a common hallmark, the accumulation of characteristic protein aggregates, known as Lewy bodies (LB) in PD, and neurofibrillary tangles in AD. LBs are primarily composed of misfolded α-synuclein (aSyn), and neurofibrillary tangles are primarily composed of tau protein. Importantly, upon pathological evaluation, most AD and PD/Lewy body dementia cases exhibit mixed pathology, with the co-occurrence of both LB and neurofibrillary tangles, among other protein inclusions. Recent studies suggest that both aSyn and tau pathology can spread and propagate through neuronal connections. Therefore, it is important to investigate the mechanisms underlying aggregation and propagation of these proteins for the development of novel therapeutic strategies. Here, we assessed the effects of different pharmacological interventions on the aggregation and internalization of tau and aSyn. We found that anle138b and fulvic acid decrease aSyn and tau aggregation, that epigallocatechin gallate decreases aSyn aggregation, and that dynasore reduces tau internalization. Establishing the effects of small molecules with different chemical properties on the aggregation and spreading of aSyn and tau will be important for the development of future therapeutic interventions.

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Section: Resultsmentioning

confidence: 74%

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Dominguez-Meijide

Vasili²,

König³

et al. 2020

Sci Rep

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“…To this end, we exploited the tendency to oligomerize that CAST1/ERC2 and other CAZ proteins have when overexpressed in neurons or heterologous cells [19,39]. These oligomers are observed as large intracellular fluorescent clusters (GFP- or mRFP-tagged) [19,39] and a similar strategy was used to study the oligomerization of gephyrin [7] and alpha-synuclein [40].…”

Section: Resultsmentioning

confidence: 99%

Serine–Arginine Protein Kinase SRPK2 Modulates the Assembly of the Active Zone Scaffolding Protein CAST1/ERC2

Arancibia

Lira

Cruz

et al. 2019

Cells

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Neurons release neurotransmitters at a specialized region of the presynaptic membrane, the active zone (AZ), where a complex meshwork of proteins organizes the release apparatus. The formation of this proteinaceous cytomatrix at the AZ (CAZ) depends on precise homo- and hetero-oligomerizations of distinct CAZ proteins. The CAZ protein CAST1/ERC2 contains four coiled-coil (CC) domains that interact with other CAZ proteins, but also promote self-assembly, which is an essential step for its integration during AZ formation. The self-assembly and synaptic recruitment of the Drosophila protein Bruchpilot (BRP), a partial homolog of CAST1/ERC2, is modulated by the serine-arginine protein kinase (SRPK79D). Here, we demonstrate that overexpression of the vertebrate SRPK2 regulates the self-assembly of CAST1/ERC2 in HEK293T, SH-SY5Y and HT-22 cells and the CC1 and CC4 domains are involved in this process. Moreover, the isoform SRPK2 forms a complex with CAST1/ERC2 when co-expressed in HEK293T and SH-SY5Y cells. More importantly, SRPK2 is present in brain synaptic fractions and synapses, suggesting that this protein kinase might control the level of self-aggregation of CAST1/ERC2 in synapses, and thereby modulate presynaptic assembly.

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“…Furthermore, MALDI-TOF mass spectrometry, ITC (Isothermal Titration Calorimetry) and MD analyses show that the aromatic residues of αSyn and the guanidine moiety of arginine interact via cation-π forces. Finally, arginine protective effect against αSyn toxicity was also proven in HeLa and SH-SY5Y cells line (S. Ghosh et al, 2018).…”

Section: Argininementioning

confidence: 96%

“…Glutamate is an excitatory neurotransmitter whose concentration in blood is around 50 µM. In the brain, it is the precursor of glutamine in presynaptic terminals and glial cells (Ghosh et al, 2018). Importantly, glutamate is shown to influence αSyn conformation and promote its aggregation.…”

Section: Glutamatementioning

confidence: 99%

α-Synuclein: An All-Inclusive Trip Around its Structure, Influencing Factors and Applied Techniques

et al. 2021

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Alpha-synuclein (αSyn) is a highly expressed and conserved protein, typically found in the presynaptic terminals of neurons. The misfolding and aggregation of αSyn into amyloid fibrils is a pathogenic hallmark of several neurodegenerative diseases called synucleinopathies, such as Parkinson’s disease. Since αSyn is an Intrinsically Disordered Protein, the characterization of its structure remains very challenging. Moreover, the mechanisms by which the structural conversion of monomeric αSyn into oligomers and finally into fibrils takes place is still far to be completely understood. Over the years, various studies have provided insights into the possible pathways that αSyn could follow to misfold and acquire oligomeric and fibrillar forms. In addition, it has been observed that αSyn structure can be influenced by different parameters, such as mutations in its sequence, the biological environment (e.g., lipids, endogenous small molecules and proteins), the interaction with exogenous compounds (e.g., drugs, diet components, heavy metals). Herein, we review the structural features of αSyn (wild-type and disease-mutated) that have been elucidated up to present by both experimental and computational techniques in different environmental and biological conditions. We believe that this gathering of current knowledge will further facilitate studies on αSyn, helping the planning of future experiments on the interactions of this protein with targeting molecules especially taking into consideration the environmental conditions.

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Small Molecules Attenuate the Interplay between Conformational Fluctuations, Early Oligomerization and Amyloidosis of Alpha Synuclein

Cited by 28 publications

References 52 publications

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Serine–Arginine Protein Kinase SRPK2 Modulates the Assembly of the Active Zone Scaffolding Protein CAST1/ERC2

α-Synuclein: An All-Inclusive Trip Around its Structure, Influencing Factors and Applied Techniques

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