White MA, Kim E, Duffy A, Adalbert R, Phillips BU, Peters OM, Stephenson J, Yang S, Massenzio F, Lin Z, Andrews S, Segonds-Pichon A, Metterville J, Saksida LM, Mead R, Ribchester RR, Barhomi Y, Serre T, Coleman MP, Fallon JR, Bussey TJ, Brown RH Jr, Sreedharan J. TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD. Nat Neurosci. 2018 Apr;21(4):552-563. Epub 2018 Mar 19 PubMed.
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RIKEN Center for Brain Science
This is a smart approach because there will be no overexpression artifacts.
View all comments by Takaomi SaidoStanford University
Stanford University
This is an important new paper. The authors created a TDP-43 knock-in mouse with the ALS-associated mutation Q331K. Other labs have used BAC (bacterial artificial chromosome) systems or large regions of the human TARDBP genomic region to introduce mutant TDP-43 into mice at near-normal levels (Swarup et al., 2011; Mutihac et al., 2015). Another group knocked in human TDP-43 cDNA with an ALS-causing mutation into the mouse Tardbp locus (encoding TDP-43) (Stribl et al., 2014). There are also knock-in TDP-43 rat models and many other transgenic TDP-43 mouse models where TDP-43 is expressed at much higher levels. The advantage of this model is that it is a single base-pair knock-in into the endogenous mouse Tardbp locus.
Similar to other TDP-43 mouse models without high levels of TDP-43 overexpression, the authors demonstrate mild motor and cognitive impairment phenotypes as well as gene expression changes. The behavioral impairments are convincingly demonstrated by an array of behavioral tests.
The TDP-43 mouse models with strong behavioral and pathological phenotypes also have very high levels of TDP-43 overexpression. This new mouse model will be useful in investigating the TDP-43 disease cascade in a more physiological system. For example, the result showing selective vulnerability of parvalbumin interneurons is very interesting. This kind of cell-type-specific result would not be nearly as convincing in a transgenic mouse line using an exogenous, strong promoter with its own pattern of differential expression.
The authors performed RNA analysis by laser capture of motor neurons in the spinal cord and by using whole-tissue analysis in the frontal cortex. They found differential gene expression and splicing changes in both contexts, but much more so for the whole-tissue analysis in the frontal cortex. The whole-tissue analysis has the added confound of possible differences in the cellular makeup of the tissue (such as selective death of parvalbumin neurons). However, this technique is very often used and the data are still interesting and informative.
The variability in some of the behavioral deficits in the authors’ mutant mice could be a key advantage and offer an opportunity to harness that variation to discover disease modifiers. For example, the results comparing mutant mice that are deficient in marble burying to those who are not is particularly intriguing. One particular gene caught our attention. The authors found that ataxin-2 expression is reduced in the knock-in mice that are able to bury marbles and elevated in those that are defective in marble burying behavior. Ataxin-2 has previously been connected to TDP-43 and human disease. Lowering levels of ataxin-2 is sufficient to suppress TDP-43 toxicity in yeast, flies, and mice (Elden et al., 2010; Becker et al., 2017). In humans, intermediate-length polyQ expansions in ataxin-2 increase risk for ALS (Elden et al., 2010). The intermediate-length polyQ expansions increase the stability of ataxin-2 (Hart and Gitler, 2012), which is expected to increase levels of ataxin-2.
The authors’ results showing that lower ataxin-2 levels correlate with less severe TDP-43 phenotypes and higher ataxin-2 levels correlate with more severe TDP-43 phenotypes are interesting. Now the challenge (and opportunity) will be to chase down the mechanisms regulating ataxin-2 expression levels, be it at the transcriptional, post-transcriptional, translational, or post-translational level. If we can identify the upstream regulators of ataxin-2 levels, then targeting those regulators could provide a therapeutic opportunity.
References:
Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, Messing J, Kim HJ, Soriano A, Auburger G, Pulst SM, Taylor JP, Rigo F, Gitler AD. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature. 2017 Apr 20;544(7650):367-371. Epub 2017 Apr 12 PubMed.
Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, Padmanabhan A, Clay-Falcone D, McCluskey L, Elman L, Juhr D, Gruber PJ, Rüb U, Auburger G, Trojanowski JQ, Lee VM, Van Deerlin VM, Bonini NM, Gitler AD. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010 Aug 26;466(7310):1069-75. PubMed.
Hart MP, Gitler AD. ALS-associated ataxin 2 polyQ expansions enhance stress-induced caspase 3 activation and increase TDP-43 pathological modifications. J Neurosci. 2012 Jul 4;32(27):9133-42. PubMed.
Mutihac R, Alegre-Abarrategui J, Gordon D, Farrimond L, Yamasaki-Mann M, Talbot K, Wade-Martins R. TARDBP pathogenic mutations increase cytoplasmic translocation of TDP-43 and cause reduction of endoplasmic reticulum Ca²⁺ signaling in motor neurons. Neurobiol Dis. 2015 Mar;75:64-77. Epub 2014 Dec 17 PubMed.
Stribl C, Samara A, Trümbach D, Peis R, Neumann M, Fuchs H, Gailus-Durner V, Hrabě de Angelis M, Rathkolb B, Wolf E, Beckers J, Horsch M, Neff F, Kremmer E, Koob S, Reichert AS, Hans W, Rozman J, Klingenspor M, Aichler M, Walch AK, Becker L, Klopstock T, Glasl L, Hölter SM, Wurst W, Floss T. Mitochondrial dysfunction and decrease in body weight of a transgenic knock-in mouse model for TDP-43. J Biol Chem. 2014 Apr 11;289(15):10769-84. Epub 2014 Feb 10 PubMed.
Swarup V, Phaneuf D, Bareil C, Robertson J, Rouleau GA, Kriz J, Julien JP. Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments. Brain. 2011 Sep;134(Pt 9):2610-26. Epub 2011 Jul 13 PubMed.
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