In the study of amyotrophic lateral sclerosis, lower motor neurons in the spine have received the lion's share of attention—but now there is a tool to focus on the role of upper motor neurons in the cortex. Researchers have developed a mouse line expressing green fluorescent protein (GFP) mostly in that population, they report in the May 1 Journal of Neuroscience. The new model, available in healthy mice and those toting an ALS-linked SOD1 mutation, should allow researchers to better understand the role of corticospinal motor neurons in health and disease, hopes senior author Hande Ozdinler of the Northwestern University Feinberg School of Medicine in Chicago, Illinois. First authors were Marina Yasvoina and Baris Genç.

“My goal is to recruit more people to the upper motor neuron field,” Ozdinler said. She has already received dozens of requests from researchers interested in the mice.

Corticospinal motor neurons (CSMNs) integrate signals from many neural circuits and send instructions on to the motor neurons in the spine. To distinguish CSMN from nearby, similar-looking neurons, the team attached GFP to the promoter for ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a de-ubiquitinating enzyme stably expressed in CSMNs. They confirmed the label was specific for CSMN via molecular markers, electrophysiology, and retrograde labeling of the neurons. They also showed that the labeled population degenerates in mSOD1 mice.

Unexpectedly, the UCHL1-GFP construct also lit up about 15 percent of neurons in spinal cord as well. The researchers determined that the label specifically tagged motor neurons that resist degeneration in mSOD1 mice. It will be interesting to investigate why the cortical population is sensitive and the spinal one resistant, Ozdinler said.

The new model has already yielded insights. Coauthor Javier Jara observed that GFP-labeled CSMNs degenerate very early in the disease course of mSOD1 mice; their dendrites fill up with autophagosomes. This contradicts a popular theory that ALS starts at the neuromuscular junction and axons die back from that point. It appears that the upper motor neurons are also affected right at the start. “The whole motor neuron circuitry collapses,” Ozdinler said.—Amber Dance


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Further Reading


  1. . Differential effects of UCHL1 modulation on alpha-synuclein in PD-like models of alpha-synucleinopathy. PLoS One. 2012;7(4):e34713. PubMed.
  2. . Control of BACE1 degradation and APP processing by ubiquitin carboxyl-terminal hydrolase L1. J Neurochem. 2012 Mar;120(6):1129-38. PubMed.
  3. . UCHL1 (PGP 9.5): neuronal biomarker and ubiquitin system protein. Prog Neurobiol. 2010 Mar;90(3):327-62. PubMed.
  4. . Identification and preliminary characterization of ubiquitin C terminal hydrolase 1 (UCHL1) as a biomarker of neuronal loss in aneurysmal subarachnoid hemorrhage. J Neurosci Res. 2010 May 15;88(7):1475-84. PubMed.

Primary Papers

  1. . eGFP expression under UCHL1 promoter genetically labels corticospinal motor neurons and a subpopulation of degeneration-resistant spinal motor neurons in an ALS mouse model. J Neurosci. 2013 May 1;33(18):7890-904. PubMed.