AUTHOR=Xiang Haoran 

TITLE=The interplay between α-synuclein aggregation and necroptosis in Parkinson’s disease: a spatiotemporal perspective

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 19 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1567445

DOI=10.3389/fnins.2025.1567445

ISSN=1662-453X

ABSTRACT=Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the death of dopaminergic neurons and the aggregation of alpha-synuclein (α-Syn). It presents with prominent motor symptoms, and by the time of diagnosis, a significant number of neurons have already been lost. Current medications can only alleviate symptoms but cannot halt disease progression. Studies have confirmed that both dopaminergic neuronal loss and α-Syn aggregation are associated with necroptosis mechanisms. Necroptosis, a regulated form of cell death, has been recognized as an underexplored hotspot in PD pathogenesis research. In this review, we propose a spatiotemporal model of PD progression, highlighting the interactions between α-Syn aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation and necroptosis. These processes not only drive motor symptoms but also contribute to early non-motor symptoms, offering insights into potential diagnostic markers. Finally, we touch upon the therapeutic potential of necroptosis inhibition in enhancing current PD treatments, such as L-Dopa. This review aims to provide a new perspective on the pathogenesis of PD and to identify avenues for the development of more effective therapeutic strategies.