CPT1C-dependent regulation of GluA1 trafficking under metabolic stress

Abstract

Carnitine palmitoyltransferase 1C (CPT1C) is the brain-specific isoform of the CPT1 family which is located at the endoplasmic reticulum (ER) of neurons and exhibits low catalytic activity, but still maintains the capacity to bind the metabolic intermediary malonyl-CoA (which levels highly fluctuate depending on the energetic status). CPT1C controls spine maturation and spatial learning, mainly through regulating synthesis and trafficking of the major AMPA receptor (AMPAR) subunit: GluA1. AMPARs mediate fast excitatory neurotransmission in the brain, and play a key role in synaptic plasticity. Some authors proposed CPT1C as a malonyl-CoA sensor, though whether this sensing is involved in AMPAR trafficking remains unknown. In the current PhD project, GluA1 surface expression was examined in cortical neurons under different metabolic stresses known to affect intracellular malonyl-CoA levels, such as glucose starvation. Moreover, CPT1C is known to interact with the phosphatidyl-inositol-4-phosphate (PI(4)P) phosphatase SAC1, which regulates vesicular transport, including GluA1 transport, by modulating the PI(4)P pool at the trans Golgi network (TGN). For that, the putative role of CPT1C in regulating SAC1 functionality under energetic stress was also evaluated. The results obtained in this thesis demonstrate

that CPT1C is able to sense malonyl-CoA and consequently modulate GluA1 trafficking through SAC1. Under basal conditions, CPT1C downregulated SAC1 activity, which was necessary for proper GluA1 trafficking. Under low malonyl-CoA levels, CPT1C favored SAC1 translocation to the ER-TGN contact sites and released its inhibition on SAC1, which decreased the Golgi PI(4)P pool and caused the retention of GluA1 at TGN. This PhD study reveals that GluA1 trafficking is regulated by CPT1C sensing of malonyl-CoA and describes the first inhibitor of SAC1 activity, which shed light on how nutrients and energy metabolism can affect synaptic function and cognition.