Understanding the influence of TLR-mediated immune system on necroptosis-induced neurodegeneration in Parkinson’s disease

Abstract

Neurodegeneration is a hallmark of various neurological disorders, including Parkinson’s disease (PD), Alzheimer’s disease (AD), stroke, and neurotropic viral infections. Although the precise etiology remains unclear, multiple pathological mechanisms contribute to disease progression, including mitochondrial dysfunction, protein aggregation, calcium excitotoxicity, endoplasmic reticulum (ER) stress, oxidative stress, immune system activation, and neuroinflammation. Among these, the immune response plays a crucial role in disease pathogenesis, acting as a defense mechanism against damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), and toxic molecular species. Chronic immune activation, particularly of microglia, is a defining feature of neuroinflammation, which involves both innate and adaptive immune responses. In the central nervous system (CNS), microglia-mediated neuroinflammation leads to the release of proinflammatory cytokines, exacerbating neuronal damage. Necroptosis, a regulated form of programmed cell death, has been implicated in neuroinflammatory disorders, including PD. Persistent microglial activation in response to aggregated proteins stimulates various microglial receptors, which includes Toll-like receptor 4 (TLR4), that play a pivotal role in necroptosis activation via the myeloid differentiating primary response gene 88 (MYD88)-independent pathway. This review explores how immune system-mediated receptor activation triggers cell death pathways, with a focus on TLR-induced necroptosis in PD. In addition, we also discuss various downstream molecular mechanisms linking TLR signaling to necroptosis and discuss the potential of TLRs as therapeutic targets, offering insights for developing neuroprotective strategies in neurodegenerative diseases (NDDS).