Scientists Take A Stab At Modeling ALS Using A TDP-43 Bac

Bac to basics. A new mouse model may help elucidate key aspects of ALS including the loss of NMJ integrity. [Courtesy of the Wellcome Collection, CC BY 4.0].

A new mouse model may help scientists elucidate early stages of ALS, including sporadic disease. The model, developed by Kevin Talbot and colleagues at the University of Oxford in England, exhibits key signs of ALS including progressive motor deficits and loss of muscle strength.

The mice, harboring two copies of the ALS-linked M337V human TDP-43 gene, develop symptoms at about 6 months. And by 9 to 12 months, the neuromuscular junctions began to crumble. No microglia-mediated neuroinflammation or cytoplasmic TDP-43 aggregates could be detected.

The BAC transgenic mice carry the complete human TDP-43 locus including its regulatory regions.

The model is one of a growing number of mice that exhibit key features of the human disease without overexpressing the disease gene (see May 2016, November 2017, December 2017, May 2018 news; Liu et al., 2016; Devoy et al., 2017; Fratta et al., 2018).

The study is published online on October 2 in Neurobiology of Disease.

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To obtain these ALS model mice for studies in your laboratory, check out this page on the Jackson Laboratory website.

Featured Paper

Gordon D, Dafinca R, Scaber J, Alegre-Abarrategui J, Farrimond L, Scott C, Biggs D, Kent L, Oliver PL, Davies B, Ansorge O, Wade-Martins R, Talbot K. Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction. Neurobiol Dis. 2018 Oct 2;121:148-162. [PubMed].

References

Fratta P, Sivakumar P, Humphrey J, Lo K, Ricketts T, Oliveira H, Brito-Armas JM, Kalmar B, Ule A, Yu Y, Birsa N, Bodo C, Collins T, Conicella AE, Mejia Maza A, Marrero-Gagliardi A, Stewart M, Mianne J, Corrochano S, Emmett W, Codner G, Groves M, Fukumura R, Gondo Y, Lythgoe M, Pauws E, Peskett E, Stanier P, Teboul L, Hallegger M, Calvo A, Chiò A, Isaacs AM, Fawzi NL, Wang E, Housman DE, Baralle F, Greensmith L, Buratti E, Plagnol V, Fisher EM, Acevedo-Arozena A. Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis. EMBO J. 2018 Jun 1;37(11). pii: e98684. [PubMed].

Devoy A, Kalmar B, Stewart M, Park H, Burke B, Noy SJ, Redhead Y, Humphrey J, Lo K, Jaeger J, Mejia Maza A, Sivakumar P, Bertolin C, Soraru G, Plagnol V, Greensmith L, Acevedo Arozena A, Isaacs AM, Davies B, Fratta P, Fisher EMC. Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in ‘FUSDelta14’ knockin mice. Brain. 2017 Nov 1;140(11):2797-2805. [PubMed].

Liu Y, Pattamatta A, Zu T, Reid T, Bardhi O, Borchelt DR, Yachnis AT, Ranum LP. C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Neuron. 2016 May 4;90(3):521-34. [PubMed].

 Further Reading

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. [PubMed].

disease-als tdp-43 topic-newmethods
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