Le NT, Chang L, Kovlyagina I, Georgiou P, Safren N, Braunstein KE, Kvarta MD, Van Dyke AM, LeGates TA, Philips T, Morrison BM, Thompson SM, Puche AC, Gould TD, Rothstein JD, Wong PC, Monteiro MJ. Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations. Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):E7580-E7589. Epub 2016 Nov 9 PubMed.
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UMC Utrecht
There have been lots of studies that try to show how TDP-43 inclusions arise, what their role in disease is, and how (aggregated) TDP-43 can be effectively cleared from cells. There is still a lot of debate on what the exact contribution of different protein degradation pathways is. A link between disturbed proteostasis and TDP-43 pathology has always been clear, but to my knowledge, previously generated UBQLN2 mutant mice did not develop TDP-43 inclusions at all (and of course not all available rodent models of ALS do). Therefore, it would be very interesting to find out how UBQLN2 controls this process in vivo and to study the consequences of this secondary TDP-43 aggregation.
View all comments by Mark VerheijenUniversity of Tübingen and DZNE AG Neumann
These are certainly interesting novel mouse models for future studies on ALS/FTD pathogenesis. Several aspects seen in these novel mouse models confirm previous findings in comparable transgenic mouse and rat models, namely that overexpression of UBQLN2 leads to accumulation of ubiquilin 2 together with other proteins of the ubiquitin/proteasome pathway consistently in the hippocampus, which results in cell loss and impaired cognitive function (Gorrie et al., 2014; Wu et al., 2015; Huang et al., 2016). Notably, these novel mouse lines also show an additional motor neuron phenotype and motor neuron degeneration, which is very likely simply due to the fact that the use of Thy1 as a promoter in these novel mice leads to a very strong expression of the transgene in the spinal cord (other transgenic models which either use CamKII or the endogenous UBQLN2 promoter, as also discussed by the authors). As always, one has to be very cautious with interpreting results from overexpressing models, and particularly those with ectopic expression, with respect to their relevance in understanding the human diseases.
Nevertheless, and independent from this concern, it is very interesting that in the spinal cord, the overexpression of UBQLN2 mutations leads to TDP-43 pathology. This is not the case in other regions, such as the hippocampus, which is also affected by cell loss in these mice in agreement with lack of TDP-43 pathology in other UBQLN2 transgenic models. This suggests that TDP-43 aggregation per se might not be a crucial step required for mediating cell death in ALS/FTD cases with UBQLN2 mutations—at least not in all cell types.
It will be interesting to see follow-up investigations in these mouse lines to further define the TDP-43 pathology (e.g., are the cytoplasmic inclusions composed of hyperphosphorylated TDP-43?) and particularly the link between TDP-43 accumulation and cell death of motor neurons (e.g., is it a bystander or directly linked to cell death?) and to dissect the “TDP-43 independent” mechanisms of toxicity upon overexpression of UBQLN2 mutations.
References:
Gorrie GH, Fecto F, Radzicki D, Weiss C, Shi Y, Dong H, Zhai H, Fu R, Liu E, Li S, Arrat H, Bigio EH, Disterhoft JF, Martina M, Mugnaini E, Siddique T, Deng HX. Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2. Proc Natl Acad Sci U S A. 2014 Oct 7;111(40):14524-9. Epub 2014 Sep 22 PubMed.
Wu Q, Liu M, Huang C, Liu X, Huang B, Li N, Zhou H, Xia XG. Pathogenic Ubqln2 gains toxic properties to induce neuron death. Acta Neuropathol. 2015 Mar;129(3):417-28. Epub 2014 Nov 12 PubMed.
Huang B, Wu Q, Zhou H, Huang C, Xia XG. Increased Ubqln2 expression causes neuron death in transgenic rats. J Neurochem. 2016 Oct;139(2):285-293. PubMed.
View all comments by Manuela NeumannStanford University - School of Medicine
Li et al. have developed a series of new mouse lines in which either wild-type (WT) or two ALS/FTD-associated mutated forms (P497S and P506T) of the human UBQLN2 gene are overexpressed broadly in neurons. The expression of the mutated but not the WT protein leads to the formation and progressive accumulation of UBQLN2-positive inclusions in several brain and spinal cord regions. This model recapitulates several key degenerative phenotypes of human ALS, such as a loss of lower motor neurons, muscle denervation/atrophy, gliosis, and impairments in muscle strength and motor tasks. Most excitingly, the model develops TDP43 pathology (nuclear clearance and formation of cytoplasmic inclusions) in motor neurons, a key histopathological hallmark observed in a majority of human ALS cases. Additionally, the authors report neuronal cell loss in other CNS areas such as the hippocampus and associated impairments in learning and memory tasks. Interestingly, no TDP43 pathology was observed in neurons other than the spinal cord motor neurons.
These new mouse lines could prove to be a valuable in vivo tool to decipher how UBQLN2 mutations cause the degenerative disease phenotypes. The UBQLN2 mutant mice can be used to investigate the exact time course of, and connection between, histopathological features such as UBQLN2 inclusion formation, TDP43 pathology, muscle denervation, neuronal cell loss, and gliosis. Further, they could be used to test potential therapeutic interventions targeting UBQLN2 expression or accumulation specifically.
More broadly, a model that faithfully reproduces key hallmarks of ALS/FTD potentially could be used to test more global therapeutic interventions, such as targeting mislocalized TDP43 in the absence of TDP43 overexpression, or therapeutics aimed at promoting neuronal survival or preventing neuroinflammation.
View all comments by Gregor BieriMake a Comment
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