1. Corticospinal Motor Neurons Are Susceptible to Increased ER Stress and Display Profound Degeneration in the Absence of UCHL1 Function.
- Author
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Jara JH, Genç B, Cox GA, Bohn MC, Roos RP, Macklis JD, Ulupınar E, and Özdinler PH
- Subjects
- Afferent Pathways physiology, Age Factors, Animals, Animals, Newborn, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Disease Models, Animal, Female, Gene Expression Regulation genetics, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Motor Cortex metabolism, Muscle Strength genetics, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Ubiquitin Thiolesterase genetics, Endoplasmic Reticulum Stress genetics, Nerve Degeneration genetics, Nerve Degeneration pathology, Spinal Cord cytology, Ubiquitin Thiolesterase deficiency
- Abstract
Corticospinal motor neurons (CSMN) receive, integrate, and relay cerebral cortex's input toward spinal targets to initiate and modulate voluntary movement. CSMN degeneration is central for numerous motor neuron disorders and neurodegenerative diseases. Previously, 5 patients with mutations in the ubiquitin carboxy-terminal hydrolase-L1 (UCHL1) gene were reported to have neurodegeneration and motor neuron dysfunction with upper motor neuron involvement. To investigate the role of UCHL1 on CSMN health and stability, we used both in vivo and in vitro approaches, and took advantage of the Uchl1(nm3419) (UCHL1(-/-)) mice, which lack all UCHL1 function. We report a unique role of UCHL1 in maintaining CSMN viability and cellular integrity. CSMN show early, selective, progressive, and profound cell loss in the absence of UCHL1. CSMN degeneration, evident even at pre-symptomatic stages by disintegration of the apical dendrite and spine loss, is mediated via increased ER stress. These findings bring a novel understanding to the basis of CSMN vulnerability, and suggest UCHL1(-/-) mice as a tool to study CSMN pathology., (© The Author 2015. Published by Oxford University Press.)
- Published
- 2015
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