Corticospinal Motor Neurons Are Susceptible to Increased ER Stress and Display Profound Degeneration in the Absence of UCHL1 Function

Jara J. H., Genc B., Cox G. A., Bohn M. C., Roos R. P., Macklis J. D., ...Daha Fazla

CEREBRAL CORTEX, cilt.25, ss.4259-4272, 2015 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 25
  • Basım Tarihi: 2015
  • Doi Numarası: 10.1093/cercor/bhu318
  • Dergi Adı: CEREBRAL CORTEX
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.4259-4272
  • Anahtar Kelimeler: AAV2-mediated transduction, apical dendrite, CSMN, ER stress, AMYOTROPHIC-LATERAL-SCLEROSIS, TERMINAL HYDROLASE L1, UBIQUITIN-PROTEASOME SYSTEM, FRONTOTEMPORAL LOBAR DEGENERATION, UNFOLDED PROTEIN RESPONSE, PARKINSONS-DISEASE, NEURODEGENERATIVE DISORDERS, TRANSGENIC MICE, IN-VIVO, PGP 9.5
  • Eskişehir Osmangazi Üniversitesi Adresli: Evet

Özet

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) genewere 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 presymptomatic 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.