Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations.
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.
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.
Nhat T T
NT
Le
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.
Lydia
L
Chang
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.
Irina
I
Kovlyagina
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201.
Polymnia
P
Georgiou
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.
Nathaniel
N
Safren
Department of Pathology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Kerstin E
KE
Braunstein
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201.
Mark D
MD
Kvarta
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201.
Adam M
AM
Van Dyke
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201.
Tara A
TA
LeGates
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.
Thomas
T
Philips
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.
Brett M
BM
Morrison
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201.
Scott M
SM
Thompson
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201.
Adam C
AC
Puche
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.
Todd D
TD
Gould
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.
Jeffrey D
JD
Rothstein
Department of Pathology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Philip C
PC
Wong
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.
Mervyn J
MJ
Monteiro
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000071183:Autophagy-Related Proteins; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D020125:Mutation, Missense; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; D004268:DNA-Binding Proteins; C578077:Tardbp protein, mouse; C538988:UBQLN2 protein, mouse
ALS; TDP-43 pathology; UBQLN2; motor neuron disease