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

Le Nhat T. T.; Chang Lydia; Kovlyagina IrinaGeorgiou PolymniaSafren NathanielBraunstein Kerstin E.Kvarta Mark D.Van Dyke Adam M.LeGates Tara A.Philips ThomasMorrison Brett M.Thompson Scott M.Puche Adam C.Gould Todd D.Rothstein Jeffrey D.Wong Philip C.Monteiro Mervyn J.

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America. >Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations

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

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

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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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2016年第47期|E7580-E7589|共10页
作者
Le Nhat T. T.; Chang Lydia; Kovlyagina IrinaGeorgiou PolymniaSafren NathanielBraunstein Kerstin E.Kvarta Mark D.Van Dyke Adam M.LeGates Tara A.Philips ThomasMorrison Brett M.Thompson Scott M.Puche Adam C.Gould Todd D.Rothstein Jeffrey D.Wong Philip C.Monteiro Mervyn J.;
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作者单位

Univ Maryland, Sch Med, Ctr Biomed Engn & Technol, Baltimore, MD 21201 USA;

Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA;

Johns Hopkins Univ, Sch Med, Dept Pathol & Neurosci, Baltimore, MD 21287 USAUniv Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USAJohns Hopkins Univ, Sch Med, Brain Sci Inst, Baltimore, MD 21287 USAUniv Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
ALS; motor neuron disease; UBQLN2; TDP-43 pathology;

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

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