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

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

• Klíčová slova
• DPYSL5, brain malformation, corpus callosum agenesis, de novo missense variants, dendrite branching, neurodevelopmental disorder, primary neuronal cultures,
• MeSH
• ageneze corpus callosum diagnostické zobrazování   genetika   MeSH
• dítě MeSH
• dospělí MeSH
• hydrolasy chemie   genetika   MeSH
• lidé MeSH
• mentální retardace diagnostické zobrazování   genetika   MeSH
• missense mutace genetika   MeSH
• mladý dospělý MeSH
• molekulární modely MeSH
• mozeček abnormality   diagnostické zobrazování   MeSH
• neurovývojové poruchy diagnostické zobrazování   genetika   MeSH
• předškolní dítě MeSH
• proteiny asociované s mikrotubuly chemie   genetika   metabolismus   MeSH
• tubulin metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• DPYSL5 protein, human MeSH Prohlížeč
• hydrolasy MeSH
• MAP2 protein, human MeSH Prohlížeč
• proteiny asociované s mikrotubuly MeSH
• TUBB3 protein, human MeSH Prohlížeč
• tubulin MeSH