DB27: TDP-43 loss of function inhibits endosomal trafficking andalters signaling in neurons

TARDBP/TDP-43 is genetically, pathologically and mechanisti-cally linked to frontotemporal lobar degeneration (FTLD) andamyotrophic lateral sclerosis (ALS). Nuclear clearance of TDP-43into cytoplasmic aggregates is a key driver of neurodegeneration inboth diseases, but the mechanism of cell death remain elusive so far.However, deficits in organelle trafficking have been heavilyimplicated in the development of neurodegenerative diseases inrecent years. Here, we show that TDP-43 knockdown specificallyreduces number and motility of RAB11-positive recycling endo-somes in dendrites without generally disturbing organelle transport,while TDP-43 overexpression has the opposite effect. This isassociated with delayed transferrin recycling in TDP-43 knockdownneurons and decreased b2-transferrin levels in patient CSF. Wholeproteome quantification identi fied upregulation of the ESCRTcomponent VPS4B upon TDP-43 knockdown in neurons. Prevent-ing VPS4B upregulation completely restores trafficking of recyclingendosomes. Proteomic analysis revealed broad reduction in surfaceexpression of receptors and cell adhesion factors. Thus, impairedrecycling of key factors to the cell surface may contribute to TDP-43induced neurodegeneration by blocking signaling