Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.

Anterograde transport of late endosomes or lysosomes (LE/Lys) is crucial for proper axon growth. However, the role of energetic nutrients has been poorly explored. Malonyl-CoA is a precursor of fatty acids, and its intracellular levels highly fluctuate depending on glucose availability or the energy sensor AMP-activated protein kinase (AMPK). We demonstrate in HeLa cells that carnitine palmitoyltransferase 1C (CPT1C) senses malonyl-CoA and enhances LE/Lys anterograde transport by interacting with the endoplasmic reticulum protein protrudin and facilitating the transfer of Kinesin-1 from protrudin to LE/Lys. In cultured mouse cortical neurons, glucose deprivation, pharmacological activation of AMPK or inhibition of malonyl-CoA synthesis decreases LE/Lys abundance at the axon terminal, and shortens axon length in a CPT1C-dependent manner. These results identify CPT1C as a new regulator of anterograde LE/Lys transport in response to malonyl-CoA changes, and give insight into how axon growth is controlled by nutrients.

Uridine-5'-Triphosphate Partially Blocks Differentiation Signals and Favors a more Repair State in Cultured rat Schwann Cells.

Schwann cells (SCs) play a key role in peripheral nerve regeneration. After damage, they respond acquiring a repair phenotype that allows them to proliferate, migrate and redirect axonal growth. Previous studies have shown that Uridine-5'-Triphosphate (UTP) and its purinergic receptors participate in several pathophysiological responses in the nervous system. Our group has previously described how UTP induces the migration of a Schwannoma cell line and promotes wound healing. These data suggest that UTP participates in the signaling involved in the regeneration process. In the present study we evaluated UTP effects in isolated rat SCs and cocultures of SCs and dorsal root ganglia neurons. UTP reduced cAMP-dependent Krox-20 induction in SCs. UTP also reduced the N-cadherin re-expression that occurs when SCs and axons make contact. In myelinating cocultures, a non-significant tendency to a lower expression of P0 and MAG proteins in presence of UTP was observed. We also demonstrated that UTP induced SC migration without affecting cell proliferation. Interestingly, UTP was found to block neuregulin-induced phosphorylation of the ErbB3 receptor, a pathway involved in the regeneration process. These results indicate that UTP could acts as a brake to the differentiation signals, promoting a more migratory state in the repair-SCs.