Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Teil, Margaux; Arotcarena, Marie-Laure; Faggiani, Emilie; Laferrière, Florent; Bézard, Erwan; Dehay, Benjamin

doi:10.3390/biom10030391

Cited by 49 publications

(49 citation statements)

References 464 publications

(602 reference statements)

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“…In the last decade, several efforts have been made to find a disease modifying strategy to halt or slow the neurodegeneration 17 . In this context, the inhibition of α-syn aggregation by small molecules proved to be a valid approach for the development of new therapeutics for the treatment of PD and several inhibitors have been discovered through high-throughput screening campaigns and drug repositioning 18 , 19 .…”

Section: Introductionmentioning

confidence: 99%

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson’s disease

Vittorio

Adornato

Gitto

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Parkinson’s disease is one of the most common neurodegenerative disorders in elderly age. One of the mechanisms involved in the neurodegeneration appears related to the aggregation of the presynaptic protein alpha synuclein (α-syn) into toxic oligomers and fibrils. To date, no highly effective treatment is currently available; therefore, there is an increasing interest in the search of new therapeutic tools. The modulation of α-syn aggregation represents an emergent and promising disease-modifying strategy for reducing or blocking the neurodegenerative process. Herein, by combining in silico and in vitro screenings we initially identified 3-(cinnamylsulfanyl)-5-(4-pyridinyl)-1,2,4-triazol-4-amine ( 3 ) as α-syn aggregation inhibitor that was then considered a promising hit for the further design of a new series of small molecules. Therefore, we rationally designed new hit-derivatives that were synthesised and evaluated by biological assays. Lastly, the binding mode of the newer inhibitors was predicted by docking studies.

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Section: Introductionmentioning

confidence: 99%

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson’s disease

Vittorio

Adornato

Gitto

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…α-Syn has become a popular target for investigational PD therapies, with RNA interference (RNAi) strategies focusing on α-Syn repression presently at preclinical stages (50). An shRNA therapeutic achieved a 35% knockdown of SNpc α-Syn, and showed protective effects in a PD rat model without notable toxicity (51).…”

Section: Discussionmentioning

confidence: 99%

RNA pull-down-Confocal Nanoscanning (RP-CONA) detects quercetin as pri-miR-7/HuR interaction inhibitor that decreases α-Synuclein levels

Zhu

Rooney

Pham

et al. 2021

Preprint

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RNA-protein interactions are central to all gene expression processes and contribute to variety of human diseases. Therapeutic approaches targeting RNA-protein interactions have shown promising effects on some diseases that are previously regarded as ‘incurable’. Here we developed a fluorescent on-bead screening platform: RNA pull-down-Confocal Nanoscanning (RP-CONA), to identify RNA-protein interaction modulators in eukaryotic cell extracts. Using RP-CONA, we identified small molecules that disrupt the interaction between HuR, an inhibitor of brain-enriched miR-7 biogenesis, and the conserved terminal loop of pri-miR-7-1. Importantly, miR-7’s primary target is an mRNA of α-Synuclein, which contributes to aetiology of Parkinson’s disease. Our method identified a natural product quercetin as a molecule able to upregulate cellular miR-7 levels and downregulate the expression of α-Synuclein. This opens up new therapeutic avenues towards treatment of Parkinson’s disease as well as provides novel methodology to search for RNA-protein interaction modulators.

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“…These interactions reduce the amount of free SYN in the cells and thus prevent its structural transition towards pathological states. Heat shock proteins (Hsp) are molecular chaperones that assist in proper conformational binding of proteins; they display protective effect against their toxicity and counteracts aggregation [25,26]. SYN interacts with Hsp90 and Hsp70 as shown by co-immunoprecipitation [27].…”

Section: Syn and Its Physiological Associationsmentioning

confidence: 99%

A Potential Innovative Therapy for Parkinson’s Disease: Selective Destruction of the Pathological Assemblies of Alpha-Synuclein

Oláh¹,

Lehotzky²,

Szénási³

et al. 2022

Dementia in Parkinson’s Disease - Everything You Need to Know

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With the aging of the population, Parkinson’s disease poses a serious socio-economic problem; there is no effective therapy that can arrest/revert the progression of the disease. The hallmarks of Parkinson’s disease and other synucleinopathies are the disordered alpha-synuclein and TPPP/p25. These proteins have neomorphic moonlighting characteristics by displaying both physiological and pathological functions. Physiologically TPPP/p25 regulates the dynamics/stability of the microtubules and is crucial for oligodendrocyte differentiation; while alpha-synuclein is involved in neuronal plasticity modulation and synaptic vesicle pool maintenance. In healthy brain, alpha-synuclein and TPPP/p25 occur predominantly in neurons and oligodendrocytes, respectively; however, they are co-enriched and co-localized in both cell types in brain inclusions in the cases of Parkinson’s disease and multiple system atrophy, respectively. The pathomechanisms of these diseases are largely unknown; the fatal species are the small, soluble homo- and hetero-associations of alpha-synuclein. These proteins with their high conformational plasticity and chameleon feature are challenging drug targets. Nevertheless, the contact surface of TPPP/p25-alpha-synuclein assemblies has been validated as a specific drug target. This new strategy with innovative impact, namely targeting the interface of the TPPP/p25-alpha-synuclein complex, could contribute to the development of anti-Parkinson drugs with unique specificity.

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Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Cited by 49 publications

References 464 publications

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson’s disease

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson’s disease

RNA pull-down-Confocal Nanoscanning (RP-CONA) detects quercetin as pri-miR-7/HuR interaction inhibitor that decreases α-Synuclein levels

A Potential Innovative Therapy for Parkinson’s Disease: Selective Destruction of the Pathological Assemblies of Alpha-Synuclein

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