Human TDP-43 and FUS selectively affect motor neuron maturation and survival in a murine cell model of ALS by non-cell-autonomous mechanisms

Abstract

TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) were recently found to cause familial and sporadic amyotrophic lateral sclerosis (ALS). The mechanisms by which mutations within these genes cause ALS are not understood. We established murine embryonic stem cell (ESC)-based cell models that stably express the human wild-type (WT) and various ALS causing mutations of TDP-43 (A315T) and FUS (R514S, R521C and P525L). We investigated their effect on pan-neuron as well as motor neuron degeneration. Finally, non-cell-autonomous mediated neurodegeneration by muscle cells was investigated. Expression of mutant hTDP-43, but not wild-type TDP-43, as well as wild-type and mutant hFUS proteins induced neuronal degeneration with partial selectivity for motor neurons. Motor neuron loss was accompanied by abnormal neurite morphology and length. In chimeric coculture experiments with control motor neurons and mutant muscle cells (as their major target cells), we detected that mutant hTDP-43 A315T as well as wild-type and hFUS P525L expression only in muscle cells is sufficient to exert degenerative effects on control motor neurons. In conclusion, our data indicate that a selective vulnerability of motor neurons expressing the pathogenic ALS-causing genes TDP-43 and FUS, is, at least in part, mediated through non-cell-autonomous mechanisms.

Key words::

• Amyotrophic lateral sclerosis
• TAR DNA binding protein 43
• fused in sarcoma
• translocated in sarcoma
• non-cell-autonomous neurodegeneration
• neuropathology
• models
• neuromuscular disease

Acknowledgements

We acknowledge Robert H. Baloh (TDP-43) and Daisuke Ito (FUS) for providing the respective plasmids. We sincerely thank Jared Sterneckert, Susanne Höing, Lydia Wagner, Peter Reinhardt and Hans Schöler for providing the Hb9::GFP mES cells and for fruitful discussions; and Tanya Levin for critical revision of the manuscript. The work was supported in part by the ‘Deutsche Gesellschaft für Muskelerkrankungen’ to AH, the MeDDrive Programme of the Medical Faculty of the Technische Universit t Dresden to AH, the Helmholtz Virtual Institute ‘RNA dysmetabolism in ALS and FTD’ to AH and AS.

Declaration of interest: The authors report no conflict of interest in this work.

Supplementary material available online

Supplementary material, Figures 1 and 2 and Tables 1–8 to be found online at http://informahealthcare.com/doi/abs/10.3109/21678421.2015.1055275.