Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations
2016
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
UBQLN2mutations 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
UBQLN2mutations 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 protein43 in the nucleus, with concomitant formation of ubiquitin + inclusions in the cytoplasm of spinal
motor neurons. Moreover, both lines displayed denervation
muscle atrophyand age-dependent loss of
motor neuronsthat correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT
UBQLN2were mostly devoid of clinical and pathological signs of disease. These
UBQLN2mouse models provide valuable tools for identifying the mechanisms underlying ALS–FTD pathogenesis and for investigating therapeutic strategies to halt disease.
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