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.