Plant natural products targeting NLRP3 inflammasome in Parkinson's disease: Molecular activation and regulation to therapeutics

TL;DR

This review explores how plant natural products can target the NLRP3 inflammasome to reduce neuroinflammation and potentially treat Parkinson's disease.

Contribution

The paper systematically demonstrates the therapeutic potential of plant natural products in targeting the NLRP3 inflammasome for Parkinson's disease.

Findings

NLRP3 inflammasome activation is linked to chronic neuroinflammation in Parkinson's disease.

α-synuclein acts as a DAMP that activates NLRP3 via TLRs and mitochondrial dysfunction.

Plant natural products show promise as precision modulators of the NLRP3 pathway for neuroprotection.

Abstract

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the pathological accumulation of α-synuclein (α-syn), a key neuronal protein implicated in neuroinflammation and disease progression. The NOD-like receptor protein 3 (NLRP3) inflammasome, a critical component of the innate immune system, serves as a macromolecular sensor for damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Its aberrant activation drives chronic neuroinflammation, which exacerbates PD pathology. This review elucidates the molecular mechanisms underlying NLRP3 inflammasome activation and its intricate relationship with PD, emphasizing the role of α-syn as a DAMP that triggers NLRP3 via Toll-like receptors (TLRs) and mitochondrial dysfunction. The review highlights how mitochondrial impairment and lysosomal disruption amplify NLRP3 activation, creating a vicious cycle of neuroinflammation and neuronal death. Importantly, emerging evidence demonstrates that plant natural products (PNPs) can effectively target the NLRP3 inflammasome pathway, offering a promising avenue for PD therapy. This review not only establishes the NLRP3 inflammasome as a pivotal macromolecular target in PD therapy but also systematically demonstrates, from the perspectives of structural biology, immunology, and translational medicine, the significant value of PNPs as a novel class of precision neuroprotective modulators—thereby laying a theoretical foundation for developing multi-target, low-toxicity therapeutic agents against PD.

Health sciences; Medicine; Natural product chemistry; Neurology

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