Convergent programmed cell death pathways in neurodegeneration: molecular mechanisms and multimodal therapeutic strategies

Convergent Programmed Cell Death Pathways in Neurodegeneration: Molecular Mechanisms and Multimodal Therapeutic StrategiesAbstractNeurodegeneration in Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) involves the irreversible loss of specific neuronal populations. Multiple programmed cell death (PCD) modalities, including apoptosis, ferroptosis, necroptosis, pyroptosis, autophagy-induced cell death (AuICD), and PARthanatos, have been implicated in these disorders. These pathways can share drivers such as reactive oxygen species, mitochondrial dysfunction, calcium dysregulation, and pro-inflammatory signalling. Rather than examining each modality in isolation, this collection will explore how they interact, which signals may shift a cell from one death pathway toward another, and how those relationships vary across diseases and cell types.Pathological aggregates of α-synuclein, tau, TDP-43 (TAR DNA-binding protein 43), and huntingtin can engage PCD machinery and amplify neuronal and glial injury. Cell death in microglia, astrocytes, and oligodendrocytes may also propagate neuroinflammation. Despite advances in characterising individual pathways, integrative models of their shared mechanisms, regulatory hierarchy, and transitions between death modalities remain limited.This Research Topic seeks to consolidate mechanistic knowledge of convergent PCD pathways in neurodegeneration and connect these insights with multimodal neuroprotective strategies. We welcome interdisciplinary contributions spanning molecular biology, genetics, imaging, systems biology, and computational science. We are particularly interested in studies that examine pathway crosstalk or test whether targeting complementary pathways can improve disease-relevant outcomes.ScopeWe welcome submissions addressing, but not limited to, the following themes:PCD pathway crosstalk and convergence: shared molecular nodes, regulatory switches, and dynamic transitions among apoptosis, ferroptosis, necroptosis, pyroptosis, AuICD, and PARthanatos.Apoptosis in neurodegeneration: caspase cascades, Bcl-2 family dynamics, and mitochondrial outer membrane permeabilisation in PD, AD, HD, and ALS, including their links to other PCD pathways.Autophagy and lysosomal dysfunction: autophagic flux, mTOR and AMPK signalling, links to protein aggregate accumulation, and effects on other cell death responses.Ferroptosis: iron metabolism, lipid peroxidation, and GPX4 regulation across neuronal populations, including its relationship with other stress and death pathways.Necroptosis and pyroptosis: RIPK1/RIPK3/MLKL and inflammasome signalling in neurons and glia, including interactions with apoptosis and neuroinflammation.Proteinopathies as PCD modulators: how disease-associated aggregates engage or alter more than one cell death pathway.Mitochondrial dysfunction, oxidative stress, and calcium dysregulation as shared upstream drivers of PCD, and the factors that influence which pathway predominates.Glial and non-cell-autonomous PCD: how cell death and signalling among neurons, microglia, astrocytes, and oligodendrocytes contribute to the spread of injury.Experimental models: iPSC-derived neurons, brain organoids, transgenic animals, and computational approaches that help identify pathway co-activation, switching, or regulatory hierarchy.Multimodal neuroprotective strategies: combined targeting of complementary PCD pathways and comparison with single-pathway approaches.Biomarkers and translational research: molecular signatures of individual or convergent PCD activity in cerebrospinal fluid or plasma, and development of PCD-targeting therapeutic agents.Submitted manuscripts should provide mechanistic insight at the cellular and subcellular levels. Purely descriptive studies, bioinformatic analyses without experimental validation, and work unrelated to neuronal or glial pathology fall outside the scope of this Research Topic. Topic editors: Nour S Erekat, Yongqiang Chen Source: https://www.frontiersin.org/research-topics/86124/convergent-programmed-cell-death-pathways-in-neurodegeneration-molecular-mechanisms-and-multimodal-therapeutic-strategies