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

Autor:	Le NT; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201.; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201., Chang L; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201.; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201., Kovlyagina I; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201.; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201., Georgiou P; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201., Safren N; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201.; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201., Braunstein KE; Department of Pathology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21287., Kvarta MD; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201., Van Dyke AM; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201., LeGates TA; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201., Philips T; Brain Science Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287., Morrison BM; Brain Science Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287., Thompson SM; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201., Puche AC; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201., Gould TD; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201.; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201., Rothstein JD; Brain Science Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287., Wong PC; Department of Pathology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21287., Monteiro MJ; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201; monteiro@umaryland.edu.; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Nov 22; Vol. 113 (47), pp. E7580-E7589. Date of Electronic Publication: 2016 Nov 09.
DOI:	10.1073/pnas.1608432113
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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