Amyotrophic lateral sclerosis (ALS) is a fatal non-cell-autonomous neurodegenerative disease characterized by the loss of motor neurons (MNs). Mutations in CRMP4 are associated with ALS in patients, and elevated levels of CRMP4 are suggested to affect MN health in the SOD1G93A -ALS mouse model. However, the mechanism by which CRMP4 mediates toxicity in ALS MNs is poorly understood. Here, by using tissue from human patients with sporadic ALS, MNs derived from C9orf72-mutant patients, and the SOD1G93A -ALS mouse model, we demonstrate that subcellular changes in CRMP4 levels promote MN loss in ALS. First, we show that while expression of CRMP4 protein is increased in cell bodies of ALS-affected MN, CRMP4 levels are decreased in the distal axons. Cellular mislocalization of CRMP4 is caused by increased interaction with the retrograde motor protein, dynein, which mediates CRMP4 transport from distal axons to the soma and thereby promotes MN loss. Blocking the CRMP4-dynein interaction reduces MN loss in human-derived MNs (C9orf72) and in ALS model mice. Thus, we demonstrate a novel CRMP4-dependent retrograde death signal that underlies MN loss in ALS.

• Klíčová slova
• ALS, CRMP4, axonal transport, dynein, retrograde signaling,
• MeSH
• amyotrofická laterální skleróza genetika   metabolismus   MeSH
• axonální transport * MeSH
• axony metabolismus   MeSH
• buněčná smrt MeSH
• buněčné linie MeSH
• dyneiny metabolismus   MeSH
• kultivované buňky MeSH
• motorické neurony metabolismus   patologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• proteiny nervové tkáně genetika   metabolismus   MeSH
• signální transdukce MeSH
• superoxid dismutáza 1 genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• Dpysl3 protein, mouse MeSH Prohlížeč
• dyneiny MeSH
• proteiny nervové tkáně MeSH
• Sod1 protein, mouse MeSH Prohlížeč
• superoxid dismutáza 1 MeSH

Autism spectrum disorder (ASD) is a heterogeneous condition with multiple etiologies and risk factors - both genetic and environmental. Recent data demonstrate that the immune system plays an important role in prenatal brain development. Deregulation of the immune system during embryonic development can lead to neurodevelopmental changes resulting in ASD. One of the potential etiologic factors in the development of ASD has been identified as the presence of maternal autoantibodies targeting fetal brain proteins. The type of ASD associated with the presence of maternal autoantibodies has been referred to as maternal antibodies related to ASD (MAR ASD). The link between maternal autoantibodies and ASD has been demonstrated in both clinical studies and animal models, but the exact mechanism of their action in the pathogenesis of ASD has not been clarified yet. Several protein targets of ASD-related maternal autoantibodies have been identified. Here, we discuss the role of microtubule-associated proteins of the collapsin response mediator protein (CRMP) family in neurodevelopment and ASD. CRMPs have been shown to integrate multiple signaling cascades regulating neuron growth, guidance or migration. Their targeting by maternal autoantibodies could change CRMP levels or distribution in the developing nervous system, leading to defects in axon growth/guidance, cortical migration, or dendritic projection, which could play an etiological role in ASD development. In addition, we discuss the future possibilities of MAR ASD treatment.

• Klíčová slova
• CRMP2, animal models, autism spectrum disorder, maternal autoantibodies, therapy,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH