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

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.

Keywords: Parkinson’s disease; alpha-synuclein; mitochondrial dysfunction; necroptosis; neuroinflammation; oxidative stress; therapeutic strategies.

FIGURE 1

Core molecular mechanisms of autophagy, pyroptosis, ferroptosis, and necroptosis. (a) Necroptosis: TNFα binding to TNFR1 forms Complex I, where RIP1 polyubiquitination by cIAP promotes cell survival. Deubiquitination of RIP1 by CYLD facilitates the formation of Complex II, leading to CASP8 activation and apoptosis. When CASP8 is inhibited, RIPK1, RIPK3, and MLKL form the necrosome, activating MLKL and inducing necroptosis via membrane pore formation. Box 1. The core pathway and key molecular changes of necroptosis in PD. These molecular changes collectively enhance necroptosis directly or indirectly. (b) Autophagy: the ULK complex is activated in response to nutrient and energy stress, initiating VPS34-dependent PI3P production and recruitment of ubiquitin-like conjugation systems. LC3 lipidation facilitates cargo receptor recruitment (e.g., SQSTM1/P62), enabling autophagosome formation. The autophagosome expands with ATG9 and fuses with lysosomes, forming autolysosomes where degradation and recycling occur. (c) Pyroptosis: cytoplasmic sensors (e.g., NLRP1, NLRP3, AIM2) recognize PAMPs/DAMPs, activating CASP1 via ASC. CASP4/5/11 directly recognize LPS, leading to GSDMD cleavage. The N-terminal fragment of GSDMD forms membrane pores, triggering pyroptosis, potassium efflux, and the release of HMGB1 and other inflammatory mediators. (d) Ferroptosis: iron overload and lipid peroxidation drive ferroptosis. The TF-TFRC complex and ferritinophagy facilitate iron accumulation, while the ACSL4-LPCAT3-ALOX pathway promotes lipid peroxidation. Antioxidant defenses, including the Xc- system, GSH, and GPX4, counteract oxidative stress to prevent ferroptotic cell death.

FIGURE 2

Abnormal α-Syn aggregation, inflammatory responses, iron deposition, mitochondrial dysfunction, oxidative stress, and interactions involving damage-associated molecular patterns (DAMPs) collectively contribute to the initiation and progression of necroptosis in dopaminergic neurons. All arrows indicate promoting effects.

FIGURE 3

This model illustrates the dynamic interactions between mitochondrial transport impairment, α-Syn protein aggregation, neuroinflammation and necroptosis during the progression of Parkinson’s disease.