title: Axonal defects in mouse models of motoneuron disease.
abstract: Human motoneuron disease is characterized by loss of motor endplates, axonal degeneration, and cell death of motoneurons. The identification of the underlying gene defects for familial ALS, spinal muscular atrophy (SMA), and spinal muscular atrophy with respiratory distress (SMARD) has pointed to distinct pathophysiological mechanisms that are responsible for the various forms of the disease. Accumulating evidence from mouse models suggests that enhanced vulnerability and sensitivity to proapoptotic stimuli is only responsible for some but not all forms of motoneuron disease. Mechanisms that modulate microtubule assembly and the axonal transport machinery are defective in several spontaneous and ENU (ethylnitrososurea) mutagenized mouse models but also in patients with mutations in the p150 subunit of dynactin. Recent evidence suggests that axonal growth defects contribute significantly to the pathophysiology of spinal muscular atrophy. Reduced levels of the survival motoneuron protein that are responsible for SMA lead to disturbed RNA processing in motoneurons. This could also affect axonal transport of mRNAs for beta-actin and other proteins that play an essential role in axon growth and synaptic function. The local translation of specific proteins might be affected, because developing motoneurons contain ribosome-like structures in distal axons and growth cones. Altogether, the evidence from these mouse models and the new genetic data from patients suggest that axon growth and maintenance involves a variety of mechanisms, including microtubule assembly and axonal transport of proteins and ribonucleoproteins (RNPs). Thus, defects in axon maintenance could play a leading role in the development of several forms of human motoneuron disease.
authors.affiliation: Institute of Clinical Neurobiology, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Jablonka
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiese
authors.forename: Michael
authors.initials: M
authors.lastname: Sendtner
mesh_terms: D000368:Aged; D017398:Alternative Splicing / Q000502:physiology; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D001370:Axonal Transport; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D053143:Caspase 2; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000172:deficiency / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D020459:Genes, rRNA / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009154:Mutation; D020932:Nerve Growth Factor / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D048491:Proto-Oncogene Proteins A-raf; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D055532:SMN Complex Proteins; D012584:Sciatic Nerve / Q000378:metabolism; D013131:Spine / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D020934:Ciliary Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C439930:HNRNPR protein, human; D018840:HSP70 Heat-Shock Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C486686:Hnrpr protein, mouse; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C000606290:SOD1 protein, human; D014157:Transcription Factors; D014404:Tubulin; C462941:beta3 tubulin, mouse; D016875:tau Proteins; D020932:Nerve Growth Factor; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D017346:Protein Serine-Threonine Kinases; D048491:Proto-Oncogene Proteins A-raf; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D053143:Caspase 2; D020169:Caspases