Rab10 regulates the sorting of internalised TrkB for retrograde axonal transport

Abstract

The extreme, complex morphology of neurons provides an unrivalled model to study the coordination between local signalling and long-range cell responses. A cogent example is provided by the binding of brain- derived neurotrophic factor (BDNF) to its receptor TrkB, which triggers signalling cascades at axon terminals that result in responses at the level of the cell body, including modulation of gene expression. Retrograde propagation of these critical signals relies on the sorting of activated TrkB receptors to retrograde axonal transport organelles termed signalling endosomes. In this work, we show that the small GTPase Rab10 is critical for the sorting of activated TrkB receptors to axonal retrograde carriers and the propagation of neurotrophin signalling from the axon terminal to the soma. Moreover, our data indicate that Rab10 defines a novel class of axonal organelles that are mobilised towards the axon terminal upon BDNF stimulation, thus enabling the axon to dynamically adjust the retrograde signalling flow to changes in BDNF availability at the synapse.

BDNF-dependent modulation of axonal transport is selectively impaired in ALS

“…Internalised BDNF-receptor complexes induce both local [ 34 ] and long-distance signalling [ 41 ]. The former controls local translation at nerve terminals [ 42 ], whilst the latter is driven by sorting of activated Trk receptors [ 43 ] to signalling endosomes, which undergo fast retrograde axonal transport to the soma [ 44 ], with signalling endosome flux dependent on TrkB activation [ 45 ]. Hence, understanding the regulation of BDNF-signalling in MN subtypes can provide novel clues regarding selective MN vulnerability in ALS.…”

Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons

“…Cells were then resuspended in plating medium, with Minimum Essential Medium (MEM, ThermoFisher, #41090028), 10% v/v heat-inactivated horse serum, 38 mM NaCl, 0.6% v/v glucose, 1x GlutaMAX (ThermoFisher, #35050–038). Before seeding, glass coverslips and microfluidic chambers (MFCs) were prepared as previously described ( Lazo and Schiavo, 2022 ). Cells were plated either on 13 mm glass coverslips (40,000 cells) or three-compartments MFCs (100,000 cells; Fig.…”

Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons

“…Cells were then resuspended in plating medium, with Minimum Essential Medium (MEM, ThermoFisher, #41090028), 10% v/v heat-inactivated horse serum, 38 mM NaCl, 0.6% v/v glucose, 1x GlutaMAX (ThermoFisher, #35050-038). Before seeding, glass coverslips and microfluidic chambers (MFCs) were prepared as previously described (Lazo & Schiavo, 2022). Cells were plated either on 13 mm glass coverslips (40,000 cells) or three-compartments MFCs (100,000 cells; Figure 1A) coated with 1 mg/ml poly-L-lysine (Sigma-Aldrich, #P2636) in borate buffer (0.15 M, pH 8.5).…”