Research Paper Volume 11, Issue 13 pp 4354—4366
Ammonia induces calpain-dependent cleavage of CRMP-2 during neurite degeneration in primary cultured neurons
- 1 Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangzhou, China
- 2 Department of Anatomy, Medical College of Jinan University, Guangzhou, China
received: December 20, 2018 ; accepted: June 19, 2019 ; published: July 6, 2019 ;https://doi.org/10.18632/aging.102053
How to Cite
Copyright: Cai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Hyperammonemia in the CNS induces irreversible damages to neurons due to ultimate cell loss. Neurite degeneration, a primary event that leads to neuronal cell death, remains less elucidated especially in hyperammonemia circumstances. Here, we found that the administration of ammonia induced neurite degeneration in cultured cerebellar granule neurons. The resulting altered neuronal morphology, rupture of neurites, and disassembly of the cytoskeleton led to cell death. Calcein and Fluo-4 staining revealed that ammonia induced intracellular calcium dysregulation. Subsequently activated calpain cleaved CRMP-2, a microtubule assembly protein. Pharmacologically inhibition of calpain, but not caspases or GSK-3, suppressed the cleavage of CRMP-2 and reversed neurite degeneration under ammonia treatment. Exposure to ammonia decreased whereas inhibition of calpain restored the amplitude and frequency of miniature excitatory postsynaptic currents. These data suggest a mechanism by which elevated ammonia level may induce neuronal dysfunction via abnormal calcium influx and calpain-dependent CRMP-2 cleavage, leading to abnormal synaptic transmission, cytoskeletal collapse, and neurite degeneration.