Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Aug 20.
doi: 10.1007/s12035-024-04425-9. Online ahead of print.

Contactin -Associated protein1 Regulates Autophagy by Modulating the PI3K/AKT/mTOR Signaling Pathway and ATG4B Levels in Vitro and in Vivo

Yan Zou #  1 , Xiao Zhang #  2   3 , Xin-Yi Chen  3 , Xiao-Fang Ma  4 , Xiao-Yan Feng  3 , Yang Sun  3 , Tao Ma  3 , Quan-Hong Ma  5 , Xu-Dong Zhao  6   7 , De-En Xu  8   9
Affiliations

Contactin -Associated protein1 Regulates Autophagy by Modulating the PI3K/AKT/mTOR Signaling Pathway and ATG4B Levels in Vitro and in Vivo

Yan Zou et al. Mol Neurobiol. .

Abstract

Contactin-associated protein1 (Caspr1) plays an important role in the formation and stability of myelinated axons. In Caspr1 mutant mice, autophagy-related structures accumulate in neurons, causing axonal degeneration; however, the mechanism by which Caspr1 regulates autophagy remains unknown. To illustrate the mechanism of Caspr1 in autophagy process, we demonstrated that Caspr1 knockout in primary neurons from mice along with human cell lines, HEK-293 and HeLa, induced autophagy by downregulating the PI3K/AKT/mTOR signaling pathway to promote the conversion of microtubule-associated protein light chain 3 I (LC3-I) to LC3-II. In contrast, Caspr1 overexpression in cells contributed to the upregulation of this signaling pathway. We also demonstrated that Caspr1 knockout led to increased LC3-I protein expression in mice. In addition, Caspr1 could inhibit the expression of autophagy-related 4B cysteine peptidase (ATG4B) protein by directly binding to ATG4B in overexpressed Caspr1 cells. Intriguingly, we found an accumulation of ATG4B in the Golgi apparatuses of cells overexpressing Caspr1; therefore, we speculate that Caspr1 may restrict ATG4 secretion from the Golgi apparatus to the cytoplasm. Collectively, our results indicate that Caspr1 may regulate autophagy by modulating the PI3K/AKT/mTOR signaling pathway and the levels of ATG4 protein, both in vitro and in vivo. Thus, Caspr1 can be a potential therapeutic target in axonal damage and demyelinating diseases.

Keywords: AKT; ATG4B; Autophagy; Axon; Contactin-associated protein; Demyelinating disease; Golgi apparatus; LC3; MTOR; PI3K.

PubMed Disclaimer

Similar articles

See all similar articles

References

    1. Fields RD (2015) A new mechanism of nervous system plasticity: activity-dependent myelination. Nat Rev Neurosci 16:756–767. https://doi.org/10.1038/nrn4023 - DOI - PubMed - PMC
    1. Bonetto G, Belin D, and Káradóttir RT (2021) Myelin: A gatekeeper of activity-dependent circuit plasticity? Science (New York, N.Y.) 374, eaba6905. https://doi.org/10.1126/science.aba6905
    1. Xin W, Chan JR (2020) Myelin plasticity: sculpting circuits in learning and memory. Nat Rev Neurosci 21:682–694. https://doi.org/10.1038/s41583-020-00379-8 - DOI - PubMed - PMC
    1. Sherman DL, Brophy PJ (2005) Mechanisms of axon ensheathment and myelin growth. Nat Rev Neurosci 6:683–690. https://doi.org/10.1038/nrn1743 - DOI - PubMed
    1. Buttermore ED, Thaxton CL, Bhat MA (2013) Organization and maintenance of molecular domains in myelinated axons. J Neurosci Res 91:603–622. https://doi.org/10.1002/jnr.23197 - DOI - PubMed - PMC

LinkOut - more resources