TDP‐43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons

Abstract

Nuclear clearance of TDP‐43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP‐43 knockdown specifically reduces the number and motility of RAB11‐positive recycling endosomes in dendrites, while TDP‐43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP‐43‐knockdown neurons and decreased β2‐transferrin levels in patient CSF. Whole proteome quantification identified the upregulation of the ESCRT component VPS4B upon TDP‐43 knockdown in neurons. Luciferase reporter assays and chromatin immunoprecipitation suggest that TDP‐43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed the broad reduction in surface expression of key receptors upon TDP‐43 knockdown, including ErbB4, the neuregulin 1 receptor. TDP‐43 knockdown delays the surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP‐43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP‐43‐induced neurodegeneration by blocking trophic signaling.

Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis

“…Interestingly, we could not find GR dendritic type aggregation in other parts of cortex in CNS and the majority of perinuclear aggregations of poly-GR, poly-GA and poly-GP were negative for pTDP-43 in other parts of CNS. TDP-43 is increasingly known to be involved in many neuritic functions including an essential role of mRNA transport into distal neurites [2, 17], endosomal trafficking and signaling in dendrites [46], and RNA granules in dendritic arbors [27]. Additional research will be required to find why poly-GR DPRs uniquely co-localize with pTDP-43 in dendrites.…”

Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS

“…The reduction in dendrite complexity was completely rescued with ErbB4 expression, suggesting that ErbB4 is one of the key effector molecules in TDP-43-dependent motor neuron dysfunction. 31 Dynamic alteration of localization of ErbB4 immunoreactivity was observed in the motor neurons of patients with SALS; the following are of particular interest: (i) localization in the nucleolus; (ii) immunoreactivity in spheroids; and (iii) ectopic immunoreactivity in oligodendrocytes. First, the nucleolar localization of ErbB4 has been widely investigated in cancer cells, in which the Cterminal region of ErbB4 binds to nucleolin, a principal component of the nucleolus that regulates differentiation and proliferation.…”

Fibroblast Growth Factor 2‐Mediated Regulation of Neuronal Exosome Release Depends on VAMP3/Cellubrevin in Hippocampal Neurons

“…Animals were handled in accordance with the regulations of local authorities and the animal welfare committee of the Ludwig Maximilian University Munich, Germany. Rat hippocampal neurons were prepared from embryonic day 18 CD rats (Charles River) and cultivated in Neurobasal media containing 2% B27, 0.25% glutamine, and 0.125% glutamate (Invitrogen) as described before . Unless otherwise indicated, neurons were treated with 50 ng mL −1 basic fibroblast growth factor (Peprotech) diluted in PBS.…”