Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies

Menon, Sindhu; Armstrong, Sabrina; Hamzeh, Amir; Visanji, Naomi P.; Sardi, S. Pablo; Tandon, Anurag

doi:10.3389/fneur.2022.852003

Cited by 35 publications

(19 citation statements)

References 285 publications

(271 reference statements)

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“…Another polyphenol resveratrol could convert soluble oligomers and fibrils of amyloid Aβ into non-toxic aggregated species . Multiple polyphenols have been discovered to inhibit α-Syn aggregation, including curcumin, myricetin, EGCG, hydroxycinnamic acids, rosmarinic acid, and ferulic acid. ,− Furthermore, some small natural polyphenols can destabilize the preformed α-Syn aggregates in vitro …”

Section: Introductionmentioning

confidence: 99%

Curcumin Interacts with α-Synuclein Condensates To Inhibit Amyloid Aggregation under Phase Separation

Chen

Liu

2022

ACS Omega

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The amyloid aggregation of α-synuclein (α-Syn) is highly associated with Parkinson’s disease (PD). Discovering α-Syn amyloid inhibitors is one of the strategies for PD therapies. Recent studies suggested that α-Syn undergoes phase separation to accelerate amyloid aggregation. Molecules modulating α-Syn phase separation or transition have the potential to regulate amyloid aggregation. Here, we discovered that curcumin, a small natural molecule, interacts with α-Syn during phase separation. Our study showed that curcumin neither affects the formation of α-Syn condensates nor influences the initial morphology of α-Syn condensates. However, curcumin decreases the fluidity of α-Syn inside the condensates and efficiently inhibits α-Syn from turning into an amyloid. It also inhibits the amyloid aggregations of PD disease-related α-Syn E46K and H50Q mutants under phase separation. Furthermore, curcumin can destabilize preformed α-Syn amyloid aggregates in the condensates. Together, our findings demonstrate that curcumin regulates α-Syn amyloid formation during protein phase separation and reveal that α-Syn amyloid aggregation under phase separation can be modulated by small molecules.

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Section: Introductionmentioning

confidence: 99%

Curcumin Interacts with α-Synuclein Condensates To Inhibit Amyloid Aggregation under Phase Separation

Chen

Liu

2022

ACS Omega

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“…Brazilin had a strong inhibitory effect on the aggregation of Aβ, remodeling Aβ amyloid fibrils by interaction with Aβ 17–42 pentamer [22] . In the past few decades, a subset of phenolic compounds, especially the polyphenols such as curcumin, myricetin, epigallocatechin gallate, hydroxycinnamic acids, rosmarinic acid, and ferulic acid, were reported to have strong anti‐aggregation effects on α‐Syn [26–36] . Interestingly, some compounds containing only one aromatic ring can inhibit α‐Syn aggregation [37] .…”

Section: Introductionmentioning

confidence: 99%

“…[22] In the past few decades, a subset of phenolic compounds, especially the polyphenols such as curcumin, myricetin, epigallocatechin gallate, hydroxycinnamic acids, rosmarinic acid, and ferulic acid, were reported to have strong anti-aggregation effects on α-Syn. [26][27][28][29][30][31][32][33][34][35][36] Interestingly, some compounds containing only one aromatic ring can inhibit α-Syn aggregation. [37] Due to the lack of structural information, the detailed mechanisms of α-Syn-phenolic compounds' interactions remain largely unclear.…”

Section: Introductionmentioning

confidence: 99%

Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition

Chen

et al. 2022

ChemBioChem

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The aggregation of α-synuclein (α-Syn) is a critical pathological hallmark of Parkinson's disease (PD). Prevention of α-Syn aggregation has become a key strategy for treating PD. Recent studies have suggested that α-Syn undergoes liquid-liquid phase separation (LLPS) to facilitate nucleation and amyloid formation. Here, we examined the modulation of α-Syn aggregation by myricetin, a polyhydroxyflavonol compound, under the conditions of LLPS. Unexpectedly, neither the initial morphology nor the phase-separated fraction of α-Syn was altered by myricetin. However, the dynamics of α-Syn con-densates decreased upon myricetin binding. Further studies showed that myricetin dose-dependently inhibits amyloid aggregation in the condensates by delaying the liquid-to-solid phase transition. In addition, myricetin could disassemble the preformed α-Syn amyloid aggregates matured from the condensates. Together, our study shows that myricetin inhibits α-Syn amyloid aggregation in the condensates by retarding the liquid-to-solid phase transition and reveals that α-Syn phase transition can be targeted to inhibit amyloid aggregation. www.chembiochem.org

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“…Moreover, a synthetic peptide developed by United Neuroscience (UB312) that mimics the oligomeric and fibrillar forms of α-synuclein is being evaluated in a Phase I clinical trial for PD (NCT04075318) [ 123 ]. Several other antibodies that target α-synuclein are currently in Phase I trials for passive immunotherapy, including MEDI1341 (AstraZeneca, Cambridge, UK), Lu-AF82422 (Lundbeck, Copenhagen, Denmark), ABBV-0805 (AbbVie, North Chicago, IL, USA/BioArctic, Stockholm, Sweden), ABL301 (Sanofi, Singapore/ABL Bio, Seongnam, Republic of Korea), and UCB7853 (UCB Biopharma, Brussels, Belgium/Novartis, Singapore) [ 124 ].…”

Section: Resultsmentioning

confidence: 99%

Current Treatments and New, Tentative Therapies for Parkinson’s Disease

Pardo-Moreno¹,

García‐Morales

Suleiman‐Martos

et al. 2023

Pharmaceutics

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Parkinson’s disease (PD) is a neurodegenerative pathology, the origin of which is associated with the death of neuronal cells involved in the production of dopamine. The prevalence of PD has increased exponentially. The aim of this review was to describe the novel treatments for PD that are currently under investigation and study and the possible therapeutic targets. The pathophysiology of this disease is based on the formation of alpha-synuclein folds that generate Lewy bodies, which are cytotoxic and reduce dopamine levels. Most pharmacological treatments for PD target alpha-synuclein to reduce the symptoms. These include treatments aimed at reducing the accumulation of alpha-synuclein (epigallocatechin), reducing its clearance via immunotherapy, inhibiting LRRK2, and upregulating cerebrosidase (ambroxol). Parkinson’s disease continues to be a pathology of unknown origin that generates a significant social cost for the patients who suffer from it. Although there is still no definitive cure for this disease at present, there are numerous treatments available aimed at reducing the symptomatology of PD in addition to other therapeutic alternatives that are still under investigation. However, the therapeutic approach to this pathology should include a combination of pharmacological and non-pharmacological strategies to maximise outcomes and improve symptomatological control in these patients. It is therefore necessary to delve deeper into the pathophysiology of the disease in order to improve these treatments and therefore the quality of life of the patients.

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Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies

Cited by 35 publications

References 285 publications

Curcumin Interacts with α-Synuclein Condensates To Inhibit Amyloid Aggregation under Phase Separation

Curcumin Interacts with α-Synuclein Condensates To Inhibit Amyloid Aggregation under Phase Separation

Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition

Current Treatments and New, Tentative Therapies for Parkinson’s Disease

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