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

Abstract

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.A LS is a progressive neurodegenerative disorder associated with loss of upper and lower motor neurons (1, 2). The disease usually manifests in the fifth decade of life, but can occur as early as the late teens. Its hallmark symptoms are progressive muscle weakness, which usually leads to death between 3 and 5 y after first diagnosis. Some patients with ALS also develop frontotemporal dementia (FTD). Genetic findings have linked mutations in different genes to the range of symptoms seen in ALS (3, 4).A common pathologic feature in nearly all ALS cases (∼97%), including all sporadic and most familial cases, is a reduction in TAR-DNA binding protein 43 (TDP-43) in the nucleus and its accumulation in ubiquitin + inclusions in the cytoplasm of spinal motor neurons (5-8). The few exceptions where this pathology is not seen are in ALS cases linked to mutations in the SOD1 and FUS genes (7-10). This has led to speculation that pathogenesis in the vast majority of ALS cases may be mechanistically linked directly or indirectly to TDP-43 pathology (7, 11). Intriguingly, TDP-43 pathology is also a common hallmark of certain forms of FTD where the pathology is found in the brain (5,7,12).Missense mutations (P497H, P497S, P506T, P509S, or P525S) in ubiquilin 2 (UBQLN2) were identified as the cause of X-linked dominant ALS-FTD (13). The afflicted individuals had abnormal inclusions in neurons of the hippocampus and TDP-43 pathology in spinal motor neurons. Additional UBQLN2 mutations have now been identified, and interestingly, like the original mutations, encode missense mutations in the central domain of UBQLN2 protein (14-16). The function of the central domain of UBQLN2 is beginning to em...

Review: Modelling the pathology and behaviour of frontotemporal dementia

“…In Drosophila expression of both wildtype and disease‐associated UBQLN2 mutations also perturbs ubiquitin homeostasis leading to toxicity, which can be prevented by mutations that prohibit ubiquitin binding . Interestingly, TDP‐43 co‐aggregated with ubiquilin 2 in UBQLN2 mutant transgenic mice but was not associated with cognitive phenotypes , similar to their pathological association in people with ALS/FTD . Thus UBQLN2 models support the growing evidence that impaired protein degradation is a common pathogenic mechanism in FTD.…”

“…Inclusions of ubiquilin 2 were frequent in all murine models, including those overexpressing wildtype protein, though much less frequent than with the mutants [132][133][134]136,138,139]. Ubiquilin 2 inclusions are also positive for proteasome subunits and the autophagosome marker LC3-II [133,139].…”

Global proteomics ofUbqln2-based murine models of ALS

“…Ubqln2 knock-in mice containing a mutant murine Ubqln2 allele corresponding to the disease-causing P506T mutation (Hjerpe et al, 2016) and less severe than that of mice overexpressing a disease-causing mutant human P497S UBQLN2 allele (Le et al, 2016).…”

Autophagy in neurodegenerative diseases: pathogenesis and therapy

“…Ubiquilin2 (UBQLN2) , a proteasome shuttle factor, plays a key role in formation of autophagosome. Mutations in UBQLN2 lead to cognitive deficits, shortened lifespan and neuron loss in mouse models . A detailed illustration of alternations in neurodegenerative diseases in autophagic flux is shown in Figure .…”