Paranodal Instability Driven by Axonal Mitochondrial Accumulation in Ischemic Demyelination and Cognitive Decline

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2025 Mar 3

PMID 40033045

Authors

Yiwei Feng

Min Guo

Tongyao You

Minjie Zhang

Jincheng Li

Junchao Xie

Sida Han

Hongchen Zhao

Yanfeng Jiang

Yanxin Zhao

Jintai Yu

Qiang Dong

Mei Cui

Affiliations

Soon will be listed here.

Abstract

Background: Subcortical ischemic demyelination is the primary cause of vascular cognitive impairment in the elderly. However, its underlying mechanisms remain elusive.

Methods: Using a bilateral common carotid artery stenosis (BACS) mouse model and an in vitro cerebellar slice model treated with low glucose-low oxygen (LGLO), we investigated a novel mechanism of vascular demyelination.

Results: This work identified syntaphilin-mediated docking of mitochondria as the initial event preceding ischemic demyelination. This axonal insult drives paranodal retraction, myelin instability, and subsequent cognitive impairment through excessive oxidation of protein 4.1B by mitochondrial ROS. Syntaphilin knockdown reestablished the balance of mitochondrial axoplasmic transport, reduced axonal ROS burden, and consequently decreased the abnormal oxidation of protein 4.1B, an essential component that secures the Caspr1/contactin-1/NF155 complex tethered to the axonal cytoskeleton βII-Spectrin within paranodes. This ultimately protected the paranodal structure and myelin and improved cognitive function.

Conclusions: Our findings reveal a distinct pathological characteristic of ischemic demyelination and highlight the therapeutic potential of modulating axonal mitochondrial mobility to stabilize myelin structures and improve vascular cognitive impairment.

References

Debette S, Markus H . The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010; 341:c3666. PMC: 2910261. DOI: 10.1136/bmj.c3666. View

Wardlaw J, Smith C, Dichgans M . Small vessel disease: mechanisms and clinical implications. Lancet Neurol. 2019; 18(7):684-696. DOI: 10.1016/S1474-4422(19)30079-1. View

Ueno Y, Koike M, Shimada Y, Shimura H, Hira K, Tanaka R . L-carnitine enhances axonal plasticity and improves white-matter lesions after chronic hypoperfusion in rat brain. J Cereb Blood Flow Metab. 2014; 35(3):382-91. PMC: 4348379. DOI: 10.1038/jcbfm.2014.210. View

Fern R, Matute C, Stys P . White matter injury: Ischemic and nonischemic. Glia. 2014; 62(11):1780-9. DOI: 10.1002/glia.22722. View

Huang N, Li S, Xie Y, Han Q, Xu X, Sheng Z . Reprogramming an energetic AKT-PAK5 axis boosts axon energy supply and facilitates neuron survival and regeneration after injury and ischemia. Curr Biol. 2021; 31(14):3098-3114.e7. PMC: 8319057. DOI: 10.1016/j.cub.2021.04.079. View

Zhao Y, Zhang J, Zheng Y, Zhang Y, Zhang X, Wang H . NAD improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway. J Neuroinflammation. 2021; 18(1):207. PMC: 8444613. DOI: 10.1186/s12974-021-02250-8. View

Fehmi J, Scherer S, Willison H, Rinaldi S . Nodes, paranodes and neuropathies. J Neurol Neurosurg Psychiatry. 2017; 89(1):61-71. DOI: 10.1136/jnnp-2016-315480. View

McKie S, Nicholson A, Smith E, Fawke S, Caroe E, Williamson J . Altered plasma membrane abundance of the sulfatide-binding protein NF155 links glycosphingolipid imbalances to demyelination. Proc Natl Acad Sci U S A. 2023; 120(14):e2218823120. PMC: 10083573. DOI: 10.1073/pnas.2218823120. View

Djannatian M, Timmler S, Arends M, Luckner M, Weil M, Alexopoulos I . Two adhesive systems cooperatively regulate axon ensheathment and myelin growth in the CNS. Nat Commun. 2019; 10(1):4794. PMC: 6805957. DOI: 10.1038/s41467-019-12789-z. View

10.

Dutta D, Woo D, Lee P, Pajevic S, Bukalo O, Huffman W . Regulation of myelin structure and conduction velocity by perinodal astrocytes. Proc Natl Acad Sci U S A. 2018; 115(46):11832-11837. PMC: 6243273. DOI: 10.1073/pnas.1811013115. View

11.

Arancibia-Carcamo I, Attwell D . The node of Ranvier in CNS pathology. Acta Neuropathol. 2014; 128(2):161-75. PMC: 4102831. DOI: 10.1007/s00401-014-1305-z. View

12.

Manso C, Querol L, Mekaouche M, Illa I, Devaux J . Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects. Brain. 2016; 139(Pt 6):1700-12. DOI: 10.1093/brain/aww062. View

13.

Malara M, Lutz A, Incearap B, Bauer H, Cursano S, Volbracht K . SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system. Cell Mol Life Sci. 2022; 79(7):371. PMC: 9209365. DOI: 10.1007/s00018-022-04400-4. View

14.

Teigler A, Komljenovic D, Draguhn A, Gorgas K, Just W . Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebellum. Hum Mol Genet. 2009; 18(11):1897-908. PMC: 2722228. DOI: 10.1093/hmg/ddp110. View

15.

Einheber S, Meng X, Rubin M, Lam I, Mohandas N, An X . The 4.1B cytoskeletal protein regulates the domain organization and sheath thickness of myelinated axons. Glia. 2012; 61(2):240-53. PMC: 3527682. DOI: 10.1002/glia.22430. View

16.

Horresh I, Bar V, Kissil J, Peles E . Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B. J Neurosci. 2010; 30(7):2480-9. PMC: 2836844. DOI: 10.1523/JNEUROSCI.5225-09.2010. View

17.

Washida K, Hattori Y, Ihara M . Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate. Int J Mol Sci. 2019; 20(24). PMC: 6941004. DOI: 10.3390/ijms20246176. View

18.

Doussau F, Dupont J, Neel D, Schneider A, Poulain B, Bossu J . Organotypic cultures of cerebellar slices as a model to investigate demyelinating disorders. Expert Opin Drug Discov. 2017; 12(10):1011-1022. DOI: 10.1080/17460441.2017.1356285. View

19.

Han Q, Xie Y, Ordaz J, Huh A, Huang N, Wu W . Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury. Cell Metab. 2020; 31(3):623-641.e8. PMC: 7188478. DOI: 10.1016/j.cmet.2020.02.002. View

20.

Satoh Y, Endo S, Ikeda T, Yamada K, Ito M, Kuroki M . Extracellular signal-regulated kinase 2 (ERK2) knockdown mice show deficits in long-term memory; ERK2 has a specific function in learning and memory. J Neurosci. 2007; 27(40):10765-76. PMC: 6672813. DOI: 10.1523/JNEUROSCI.0117-07.2007. View