title: 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.
authors.affiliation: a Division for Neurodegenerative Diseases, Department of Neurology , Technische Universität Dresden , Dresden , Germany.|b German Centre for Neurodegenerative Diseases (DZNE) , Dresden , Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wächter
authors.affiliation: a Division for Neurodegenerative Diseases, Department of Neurology , Technische Universität Dresden , Dresden , Germany.|b German Centre for Neurodegenerative Diseases (DZNE) , Dresden , Germany.|c DFG-Centre for Regenerative Therapies Dresden Cluster of Excellence / Technische Universität Dresden , Dresden , Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Storch
authors.affiliation: a Division for Neurodegenerative Diseases, Department of Neurology , Technische Universität Dresden , Dresden , Germany.|b German Centre for Neurodegenerative Diseases (DZNE) , Dresden , Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS; C000598624:TARDBP protein, human
keywords: Amyotrophic lateral sclerosis; TAR DNA binding protein 43; fused in sarcoma; models; neuromuscular disease; neuropathology; non-cell-autonomous neurodegeneration; translocated in sarcoma