title: Calpain-dependent truncated form of TrkB-FL increases in neurodegenerative processes.
abstract: Recent findings indicate that the mechanisms that drive reshaping of the nervous system are aberrantly activated in epilepsy and several neurodegenerative diseases. The recurrent seizures in epilepsy, particularly in the condition called status epilepticus, can cause permanent neurological damage, resulting in cognitive dysfunction and other serious neurological conditions. In this study, we used an in vitro model of status epilepticus to examine the role of calpain in the degeneration of hippocampal neurons. We grew neurons on a culture system that allowed studying the dendritic and axonal domains separately from the cell bodies. We found that a recently characterized calpain substrate, the neurotrophin receptor TrkB, is cleaved in the dendritic and axonal domain of neurons committed to die, and this constitutes an early step in the neuronal degeneration process. While the full-length TrkB (TrkB-FL) levels decreased, the truncated form of TrkB (Tc TrkB-FL) concurrently increased, leading to a TrkB-FL/Tc TrkB-FL imbalance, which is thought to be causally linked to neurodegeneration. We further show that the treatment with N-acetyl-Leu-Leu-norleucinal, a specific calpain activity blocker, fully protects the neuronal processes from degeneration, prevents the TrkB-FL/Tc TrkB-FL imbalance, and provides full neuroprotection. Moreover, the use of the TrkB antagonist ANA 12 at the time when the levels of TrkB-FL were significantly decreased, totally blocked neuronal death, suggesting that Tc TrkB-FL may have a role in neuronal death. These results indicate that the imbalance of these neurotrophins receptors plays a key role in neurite degeneration induced by seizures.
authors.affiliation: Laboratorio de Neurobiología, Instituto de Investigaciones Biológicas y Tecnológicas, IIByT-CONICET-FCEFyN, Universidad Nacional de Córdoba, Av. Vélez Sarsfield 1611, Córdoba, Argentina.
authors.forename: Víctor
authors.initials: V
authors.lastname: Danelon
authors.affiliation: Laboratorio de Neurobiología, Instituto de Investigaciones Biológicas y Tecnológicas, IIByT-CONICET-FCEFyN, Universidad Nacional de Córdoba, Av. Vélez Sarsfield 1611, Córdoba, Argentina.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Montroull
authors.affiliation: Departments of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Unsain
authors.affiliation: Departments of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Barker
authors.affiliation: Laboratorio de Neurobiología, Instituto de Investigaciones Biológicas y Tecnológicas, IIByT-CONICET-FCEFyN, Universidad Nacional de Córdoba, Av. Vélez Sarsfield 1611, Córdoba, Argentina. Electronic address: dmasco@fcq.unc.edu.ar.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Mascó
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016923:Cell Death; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology; D007976:Leupeptins / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013226:Status Epilepticus / Q000378:metabolism
chemical_list: D007976:Leupeptins; D011480:Protease Inhibitors; C063261:acetylleucyl-leucyl-norleucinal; D020813:Receptor, trkB; D002154:Calpain; D002118:Calcium
keywords: Calpain; Neurite degeneration; Neuronal death; Status epilepticus; TrkB-FL; Truncated TrkB-FL