Plasmalogens regulate the AKT-ULK1 signaling pathway to control the position of the axon initial segment
Progress in Neurobiology. 2021-10-01; 205: 102123
DOI: 10.1016/j.pneurobio.2021.102123
Lire sur PubMed
Ferreira da Silva T(1), Granadeiro LS(1), Bessa-Neto D(1), Luz LL(2), Safronov BV(2), Brites P(3).
Author information:
(1)Neurolipid Biology, Instituto de Investigação e Inovação em Saúde da
Universidade do Porto – i3S, Porto, Portugal; Instituto de Biologia Molecular e
Celular – IBMC, Porto, Portugal.
(2)Instituto de Biologia Molecular e Celular – IBMC, Porto, Portugal; Neuronal
Networks Group, Instituto de Investigação e Inovação em Saúde da Universidade do
Porto – i3S, Porto, Portugal.
(3)Neurolipid Biology, Instituto de Investigação e Inovação em Saúde da
Universidade do Porto – i3S, Porto, Portugal; Instituto de Biologia Molecular e
Celular – IBMC, Porto, Portugal. Electronic address: .
The axon initial segment (AIS) is a specialized region in neurons that encompasses two essential functions, the generation of action potentials and the
regulation of the axodendritic polarity. The mechanism controlling the position of the axon initial segment to allow plasticity and regulation of neuron
excitability is unclear. Here we demonstrate that plasmalogens, the most abundant ether-phospholipid, are essential for the homeostatic positioning of the AIS. Plasmalogen deficiency is a hallmark of Rhizomelic Chondrodysplasia Punctata (RCDP) and Zellweger spectrum disorders, but Alzheimer’s and Parkinson’s disease, are also characterized by plasmalogen defects. Neurons lacking plasmalogens displaced the AIS to more distal positions and were characterized by reduced excitability. Treatment with a short-chain alkyl glycerol was able to rescue AIS positioning. Plasmalogen deficiency impaired AKT activation, and we show that inhibition of AKT phosphorylation at Ser473 and Thr308 is sufficient to induce a distal relocation of the AIS. Pathway analysis revealed that downstream of AKT, overtly active ULK1 mediates AIS repositioning. Rescuing the impaired AKT signaling pathway was able to normalize AIS position independently of the biochemical defect. These results unveil a previously unknown mechanism that couples the phospholipid composition of the neuronal membrane to the positional assembly of the AIS.
Copyright © 2021 Elsevier Ltd. All rights reserved.