title: Corticospinal Motor Neurons Are Susceptible to Increased ER Stress and Display Profound Degeneration in the Absence of UCHL1 Function.
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.
authors.affiliation: Davee Department of Neurology and Clinical Neurological Sciences.
authors.forename: Javier H
authors.initials: JH
authors.lastname: Jara
authors.affiliation: Davee Department of Neurology and Clinical Neurological Sciences.
authors.forename: Barış
authors.initials: B
authors.lastname: Genç
authors.affiliation: Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.affiliation: Neurobiology Program, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago Research Center, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Martha C
authors.initials: MC
authors.lastname: Bohn
authors.affiliation: Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, USA.
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Roos
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, UK.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Macklis
authors.affiliation: Department of Anatomy, Eskişehir Osmangazi University Medical School, Eskişehir, Turkey.
authors.forename: Emel
authors.initials: E
authors.lastname: Ulupınar
authors.affiliation: Davee Department of Neurology and Clinical Neurological Sciences Robert H. Lurie Cancer Center Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, IL 60611, USA.
authors.forename: P Hande
authors.initials: PH
authors.lastname: Özdinler
mesh_terms: D000344:Afferent Pathways / Q000502:physiology; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009044:Motor Cortex / Q000378:metabolism; D053580:Muscle Strength / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology*; D043222:Ubiquitin Thiolesterase / Q000172:deficiency* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C482860:UCHL1 protein, human; C412364:Zfp312 protein, mouse; D043222:Ubiquitin Thiolesterase
keywords: AAV2-mediated transduction; CSMN; ER stress; apical dendrite