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

Cereb Cortex. 2015 Nov;25(11):4259-72. doi: 10.1093/cercor/bhu318. Epub 2015 Jan 16.


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.

Keywords: AAV2-mediated transduction; CSMN; ER stress; apical dendrite.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Afferent Pathways / physiology
  • Age Factors
  • Animals
  • Animals, Newborn
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / genetics*
  • Female
  • Gene Expression Regulation / genetics
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Motor Cortex / metabolism
  • Muscle Strength / genetics
  • Nerve Degeneration / genetics*
  • Nerve Degeneration / pathology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Spinal Cord / cytology*
  • Ubiquitin Thiolesterase / deficiency*
  • Ubiquitin Thiolesterase / genetics


  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • UCHL1 protein, human
  • Zfp312 protein, mouse
  • Ubiquitin Thiolesterase