Novel Approaches Targeting in α-Synuclein for Parkinson's Disease: Current Progress and Future Directions for the Disease-Modifying Therapies

Brain Disorders, Journal Year: 2024, Volume and Issue: unknown, P. 100163 - 100163

Published: Sept. 1, 2024

Language: Английский

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NPT100-18A rescues mitochondrial oxidative stress and neuronal degeneration in human iPSC-based Parkinson’s model

BMC Neuroscience, Journal Year: 2025, Volume and Issue: 26(1)

Published: Jan. 28, 2025

Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein aggregates mostly consisting of misfolded alpha-synuclein (αSyn). Progressive degeneration midbrain dopaminergic neurons (mDANs) and nigrostriatal projections results in severe motor symptoms. While the preferential loss mDANs has not been fully understood yet, cell type-specific vulnerability linked to unique intracellular milieu, influenced dopamine metabolism, high demand for mitochondrial activity, increased level oxidative stress (OS). These factors have shown adversely impact αSyn aggregation. Reciprocally, aggregates, particular oligomers, can impair functions exacerbate OS. Recent drug-discovery studies identified series small molecules, including NPT100-18A, which reduce oligomerization preventing misfolding dimerization. NPT100-18A structurally similar compounds (such as NPT200-11/UCB0599, currently being assessed clinical studies) point towards promising new approach disease-modification. Induced pluripotent stem (iPSC)-derived from PD patients with monoallelic SNCA locus duplication unaffected controls were treated NPT100-18A. aggregation was evaluated biochemically reactive oxygen species (ROS) levels living using fluorescent dyes. Adenosine triphosphate (ATP) measured luminescence-based assay, neuronal death immunocytochemistry. Compared controls, patient-derived exhibited higher cytoplasmic ROS probe levels, reduced ATP-related signals, activation caspase-3, reflecting early death. NPT100-18A-treatment rescued cleaved caspase-3 control and, importantly, attenuated compartment-specific manner at concentrations, ATP signals. Our findings demonstrate that limits human vitro model PD. In addition, we provide first mechanistic insights into how antioxidant effect mitochondria might contribute neuroprotective effects

Language: Английский

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Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson’s Disease

Cellular and Molecular Neurobiology, Journal Year: 2025, Volume and Issue: 45(1)

Published: March 26, 2025

Worldwide aging has contributed to the growth of prevalence neurodegenerative diseases (NDDs), including Parkinson's disease among elderlies. The advanced destruction dopaminergic neurons in substantia nigra, due many accelerator factors brain is main mechanism disease. pathological aggregated alpha-synuclein (α-syn), a protein implicated multiple disorders, one critical this and other similar disorders. misfolding aggregation α-syn may interrupt processes, functions synaptic vesicles can lead neuronal death. This encoded by Alpha-Synuclein Gene (SNCA) mutation gene dysfunctions structure. Since, therapeutic policies that aim are promising approaches. Advances immunotherapies, molecular chaperones, therapy targeting SNCA, DNA aptamers some examples strategy. review aims comprehensively assess current knowledge evidence on pathology, genetic determinants, novel methods Parkinson,'s synucleinopathies. Continued investigation discover interventions system could result finding effective safe treatments for NDDs.

Language: Английский

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Neuroprotective potential of hispidulin and diosmin: a review of molecular mechanisms

Metabolic Brain Disease, Journal Year: 2025, Volume and Issue: 40(5)

Published: April 21, 2025

Language: Английский

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