Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linkedUBQLN2mutations

Nhat T. T. Le, Lydia Chang, Irina Kovlyagina, Polymnia Georgiou, Nathaniel Safren, Kerstin E. Braunstein, Mark D. Kvarta, Adam M. Van Dyke, Tara A. LeGates, Thomas Philips, Brett M. Morrison, Scott M. Thompson (+5 others)
2016 Proceedings of the National Academy of Sciences of the United States of America  
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
more » ... e, 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. ALS | motor neuron disease | UBQLN2 | TDP-43 pathology 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 emerge with studies showing it assists in chaperone function (17) (18) (19) and in docking the protein with different adaptors of its function (20) (21) (22) . The function of the two end domains that border the central domain is better understood. At the N terminus is a UBL domain that binds the proteasome and at the C terminus a UBA domain that binds ubiquitin moieties typically tagged onto proteins targeted for degradation. Their properties fit with the function of UBQLN proteins as shuttle factors that bind and deliver misfolded proteins to the proteasome for degradation (23, 24) . In addition to proteasomal degradation, UBQLN proteins also play a role by facilitating autophagy (25, 26) . The mechanisms by which UBQLN2 mutations cause ALS are not completely understood. Knockout of the UBQLN2 gene in rat produced no overt phenotype, ruling out simple loss of function (27). Therefore, it can be postulated that UBQLN2 mutations result in ALS endophenotypes through a gain-of-function Significance Animal models of human diseases provide important tools for mechanistic and preclinical investigations. Mutations in several genes cause ALS. One such gene is ubiquilin 2 (UBQLN2), mutations in which cause dominant inheritance of ALS with frontotemporal dementia (ALS-FTD). Several rodent models carrying UBQLN2 mutations have been described, but none develop motor neuron disease. We describe two transgenic (Tg) mouse models of ALS-FTD carrying different UBQLN2 mutations. Both models develop cognitive deficits, classic TAR-DNA binding protein 43 (TDP-43) pathology seen in ALS, and motor neuron disease. By contrast, Tg mouse lines expressing WT UBQLN2 had normal lifespans, no evidence of TDP-43 pathology, and mild signs of disease. These mouse lines provide valuable investigative tools for ALS-FTD research.
doi:10.1073/pnas.1608432113 pmid:27834214 pmcid:PMC5127348 fatcat:36lp4yh3pjc45nw4qzrttpwjwm