Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations

Nhat T.T. Le, Lydia Chang, Irina Kovlyagina, Polymnia Georgiou, Nathaniel Safren, Kerstin E. Braunstein, Mark D. Kvarta, Adam M.Van Dyke, Tara A. Legates, Thomas Philips, Brett M. Morrison, Scott M. Thompson, Adam C. Puche, Todd D. Gould, Jeffrey D. Rothstein, Philip C. Wong, Mervyn J. Monteiro*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin+ inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to halt disease.

Original languageEnglish (US)
Pages (from-to)E7580-E7589
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number47
StatePublished - Nov 22 2016
Externally publishedYes


  • ALS
  • Motor neuron disease
  • TDP-43 pathology
  • UBQLN2

ASJC Scopus subject areas

  • General


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