Cell Death Mechanisms in Parkinson's Disease

Parkinson’s disease arises from progressive loss of dopaminergic neurons in the substantia nigra, driven by multiple regulated and unregulated death pathways. Apoptosis, a form of programmed cell death involving caspase activation, is seen in early degenerative stages. Necrosis, traditionally viewed as uncontrolled, also contributes via mitochondrial failure and energy collapse. More recently, necroptosis, pyroptosis and ferroptosis have been implicated, linking receptor signalling, ion fluxes and lipid peroxidation to neuronal demise. Aggregation of α-synuclein, oxidative stress, mitochondrial dysfunction and impaired autophagy converge on these death mechanisms, while microglia and astrocytes modulate inflammatory and phagocytic responses that can either exacerbate or mitigate injury. Understanding the interplay between intrinsic neuronal pathways and glial mediators is key to designing interventions that promote survival or hinder maladaptive inflammation. Emerging strategies aim to bolster mitochondrial resilience, restore proteostasis and modulate glial phenotypes to preserve motor function globally.

Research from Nature Portfolio

Recent studies have shown that repurposing meclizine, an antihistamine, enhances glycolysis in dopaminergic cell models, increasing mitochondrial hyperpolarisation and resilience to toxin-induced injury. By upregulating glycolytic enzymes, meclizine shifts energy metabolism away from damaged oxidative phosphorylation, thereby reducing apoptotic signalling and cell loss in culture systems. This work offers a proof of principle that metabolic reprogramming can protect vulnerable neurons in Parkinsonian paradigms and suggests further investigation of metabolic modulators in vivo.

Cell Death Mechanisms in Parkinson's Disease publication trend

The graph below shows the total number of articles in cell death mechanisms in parkinson's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Apoptosis: Programmed cell death mediated by caspases, characterised by chromatin condensation and membrane blebbing.

Necrosis: Unregulated cell death due to severe insult, leading to membrane rupture and inflammation.

Necroptosis: Regulated necrotic death triggered by receptor interacting protein kinases.

Autophagy: Lysosome-mediated degradation pathway for recycling cellular components.

α-Synuclein: Neuronal protein prone to aggregation, central to Parkinson’s pathology.

Microglia: Resident immune cells of the central nervous system that mediate phagocytosis and inflammation.

Astrocytes: Glial cells that support neurons, regulate extracellular environment and participate in inflammatory responses.

References

1. Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity. Journal of Neuroinflammation (2024).
2. Dopaminergic neurons lacking Caspase-3 avoid apoptosis but undergo necrosis after MPTP treatment inducing a Galectin-3-dependent selective microglial phagocytic response. Cell Death & Disease (2024).
3. Meclizine-induced enhanced glycolysis is neuroprotective in Parkinson disease cell models. Scientific Reports (2016).