Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets
TL;DR
This review examines RCD as an integrated pathogenic network in major NDs as well as evaluating emerging therapeutic strategies that target cell death crosstalk, restore autophagy lysosomal competence, or improve delivery to the central nervous system.
Abstract
Neurodegenerative diseases (NDs) are marked by selective neuronal vulnerability and progressive failure of neural circuits. Increasing evidence indicates that neuronal loss is not driven by a single terminal event, but emerges from interacting regulated cell death (RCD) programs. These programs are closely coupled to mitochondrial injury, proteostatic collapse, lysosomal stress, metabolic imbalance, glial state transitions, and chronic neuroinflammation. Yet, how distinct death pathways are organized across cell types, disease stages, and disease‐specific microenvironments remains unresolved. This review examines RCD as an integrated pathogenic network in major NDs. Caspase and B‐cell lymphoma 2 (BCL2) family signaling, receptor‐interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain‐like protein activation, NOD‐like receptor family pyrin domain containing 3 and gasdermin signaling, GPX4‐linked lipid peroxidation control, and autophagy lysosomal failure are discussed as convergent stress response modules rather than isolated pathways. Across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, these modules shape neuronal fate through disease‐specific interactions with mitochondrial dysfunction, iron dyshomeostasis, inflammasome activation, and microglial metabolic remodeling. We further evaluate emerging therapeutic strategies that target cell death crosstalk, restore autophagy lysosomal competence, or improve delivery to the central nervous system, highlighting the importance of molecular selectivity, cellular context, disease stage, and translational feasibility.