Neuronal cell death: Apoptosis and Parthanatos

With ischemic stroke, portions of brain undergo cellular death with swelling, termed apoptosis, which causes characteristic changes on imaging studies. On the other hand, degenerative diseases such as Parkinson's cause cellular loss without apoptosis or swelling. This is termed parthanatos, because it is dependent on the Poly Adp-Ribose pathway.

The study below of a model for this type of neuronal cell loss might be used to test agents to prevent such neuronal cell death, hopefully with more success than past studies targeting apoptosis.



Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity

Jin-Chong Xu, Jing Fan, Xueqing Wang, Stephen M. Eacker, Tae-In Kam, Li Chen, Xiling Yin, Juehua Zhu, Zhikai Chi, Haisong Jiang, Rong Chen, Ted M. Dawson, and Valina L. Dawson

Science Translational Medicine 06 Apr 2016:

Vol. 8, Issue 333, pp. 333ra48, DOI: 10.1126/scitranslmed.aad0623

Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells or human inducible pluripotent stem cells that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid to FOXG1+ neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable. In human cortical neuronal cultures, excitotoxicity or ischemia due to oxygen and glucose deprivation led to cell death that was dependent on N-methyl-D-aspartate (NMDA) receptors, nitric oxide (NO), and poly(ADP-ribose) polymerase (PARP) (a cell death pathway called parthanatos that is distinct from apoptosis, necroptosis, and other forms of cell death). Neuronal cell death was attenuated by PARP inhibitors that are currently in clinical trials for cancer treatment. This culture system provides a new platform for the study of human cortical neurotoxicity and suggests that PARP inhibitors may be useful for ameliorating excitotoxic and ischemic cell death in human neurons.

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