Necroptosis is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Necroptosis is a regulated form of programmed cell death that combines features of apoptosis (programmed execution) with necrotic morphology (cell swelling and membrane rupture). Unlike apoptosis, necroptosis is caspase-independent and is mediated by the RIPK1–RIPK3–MLKL signaling axis. First identified as a "backup" death pathway when caspases are inhibited, necroptosis is now recognized as a physiologically significant process with critical roles in development, innate immunity, and disease pathogenesis. In the context of neurodegeneration, necroptosis has emerged as a major driver of neuronal loss and neuroinflammation in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis (Bhardwaj et al., 2025; Bhargava et al., 2024). [@galluzzi2011] [@degterev2005]
The core necroptosis pathway is executed by three key proteins that form the necrosome signaling complex (Linkermann & Green, 2014): [@degterev2005] [@kaiser2013]
RIPK1 (Receptor-Interacting Protein Kinase 1): A multi-domain serine/threonine kinase that serves as a molecular switch between cell survival, apoptosis, and necroptosis. RIPK1 is activated following stimulation of death receptors, particularly TNF receptor 1 (TNFR1). Under conditions where caspases (especially caspase-8) are inhibited or absent, RIPK1 autophosphorylates and recruits RIPK3 through RHIM (RIP Homotypic Interaction Motif) domain interactions. [@kaiser2013]
RIPK3 (Receptor-Interacting Protein Kinase 3): Upon RHIM-mediated binding to RIPK1, RIPK3 undergoes autophosphorylation and forms amyloid-like fibrillar signaling platforms. Activated RIPK3 then phosphorylates the downstream effector MLKL at Thr357 and Ser358 (human) or Ser345 (mouse). [@caccamo2017]
MLKL (Mixed Lineage Kinase Domain-Like Pseudokinase): The terminal executor of necroptosis. Phosphorylation by RIPK3 triggers MLKL conformational change and oligomerization. MLKL oligomers translocate to the plasma membrane, where they form pores that disrupt membrane integrity, causing cell swelling and lytic cell death. [@wang2020]
Multiple signaling pathways can initiate necroptosis (Pasparakis & Vandenabeele, 2015): [@wu2021] [@caccamo2017]
Several proteins negatively regulate necroptosis to prevent uncontrolled cell death: [@wang2020]
Necroptosis has been identified as a principal mechanism of neuronal death in Alzheimer's disease. Elevated levels of activated (phosphorylated) RIPK1, RIPK3, and MLKL have been consistently detected in postmortem AD brain tissue, with these proteins showing enhanced colocalization in affected brain regions including the hippocampus, [entorhinal cortex, and [prefrontal cortex (Bhargava et al., 2024). [@wu2021]
Key findings include: [@neurodegenerative]
In Parkinson's disease, necroptosis contributes to the selective loss of [dopaminergic neurons/cell-types/dopaminergic-neurons in the substantia nigra pars compacta: [@genes]
RIPK1, RIPK3, and MLKL are significantly elevated in MPTP-induced PD mouse models and in postmortem PD brain tissue (Yuan et al., 2019)).
Pharmacological or genetic inhibition of RIPK3 or MLKL dramatically ameliorates PD pathology by rescuing [dopaminergic neurons and restoring dopamine levels.
alpha-synuclein aggregation activates microglia/motor neuron death in ALS:
Elevated RIPK1 and RIPK3 activity is found in spinal cord [motor neurons/cell-types/motor-[neurons) of both [SOD1/proteins/sod1 mutant mice and sporadic ALS patients.
TDP-43 pathology, the hallmark of most ALS cases, may impair RNA processing of anti-necroptotic genes.
SAR443820 (DNL788), a brain-penetrant RIPK1 inhibitor developed by Sanofi/Denali Therapeutics, was tested in the Phase 2 HIMALAYA trial for ALS, though the trial did not meet its primary endpoint of change in the ALS Functional Rating Scale-Revised (Bhatt et al., 2023).
In multiple sclerosis, necroptosis contributes to oligodendrocyte death and demyelination: [@mechanisms]
The relationship between necroptosis and neuroinflammation is bidirectional and creates a self-amplifying destructive cycle (Kaczmarek et al., 2013): [@proteins]
RIPK1 is the most tractable therapeutic target in the necroptosis pathway due to its kinase-dependent activation: [@ncbi]
| Compound | Developer | Mechanism | Status | Notes | [@uniprot]
|----------|-----------|-----------|--------|-------| [@ref]
| Necrostatin-1 (Nec-1) | Academic | RIPK1 allosteric inhibitor | Preclinical tool | First-in-class; limited bioavailability |
| Necrostatin-1s (Nec-1s) | Academic | Improved Nec-1 analog | Preclinical | Better selectivity and stability |
| SAR443060 (DNL747) | Sanofi/Denali | Brain-penetrant RIPK1 inhibitor | Discontinued | Phase I safe but insufficient target engagement |
| SAR443820 (DNL788) | Sanofi/Denali | Next-gen brain-penetrant RIPK1 inhibitor | Phase 2 (MS) | Failed Phase 2 in ALS; continues in MS |
| GSK2982772 | GSK | RIPK1 inhibitor | Phase 2 (IBD, RA) | Peripheral indications |
| GFH312 | GenFleet | RIPK1 inhibitor | Phase 1 | Novel chemical scaffold |
The study of Necroptosis has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.