Netrin-1 Signaling Pathway Mechanisms in Neurodegenerative Diseases

Overview

Journal Neural Regen Res

Date 2024 Jul 11

PMID 38989931

Authors

Kedong Zhu

Hualong Wang

Keqiang Ye

Guiqin Chen

Zhaohui Zhang

Affiliations

Soon will be listed here.

Abstract

Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development. Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function. Increasing amounts of evidence highlight several key points: (1) Diminished Netrin-1 levels exacerbate pathological progression in animal models of Alzheimer's disease and Parkinson's disease, and potentially, similar alterations occur in humans. (2) Genetic mutations of Netrin-1 receptors increase an individuals' susceptibility to neurodegenerative disorders. (3) Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function. (4) Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers. These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases. Through a comprehensive review of Netrin-1 signaling pathways, our objective is to uncover potential therapeutic avenues for neurodegenerative disorders.

References

Colon-Ramos D, Margeta M, Shen K . Glia promote local synaptogenesis through UNC-6 (netrin) signaling in C. elegans. Science. 2007; 318(5847):103-6. PMC: 2741089. DOI: 10.1126/science.1143762. View

Lourenco F, Galvan V, Fombonne J, Corset V, Llambi F, Muller U . Netrin-1 interacts with amyloid precursor protein and regulates amyloid-beta production. Cell Death Differ. 2009; 16(5):655-63. PMC: 2757418. DOI: 10.1038/cdd.2008.191. View

Macedo A, Gomez C, Rebelo M, Poza J, Gomes I, Martins S . Risk Variants in Three Alzheimer's Disease Genes Show Association with EEG Endophenotypes. J Alzheimers Dis. 2021; 80(1):209-223. PMC: 8075394. DOI: 10.3233/JAD-200963. View

Lisman J, Buzsaki G, Eichenbaum H, Nadel L, Ranganath C, Redish A . Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nat Neurosci. 2017; 20(11):1434-1447. PMC: 5943637. DOI: 10.1038/nn.4661. View

Peters-Libeu C, Campagna J, Mitsumori M, Poksay K, Spilman P, Sabogal A . sAβPPα is a Potent Endogenous Inhibitor of BACE1. J Alzheimers Dis. 2015; 47(3):545-55. DOI: 10.3233/JAD-150282. View

Lengrand J, Pastushenko I, Vanuytven S, Song Y, Venet D, Sarate R . Pharmacological targeting of netrin-1 inhibits EMT in cancer. Nature. 2023; 620(7973):402-408. PMC: 7615210. DOI: 10.1038/s41586-023-06372-2. View

Hashimoto Y, Toyama Y, Kusakari S, Nawa M, Matsuoka M . An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling. J Biol Chem. 2016; 291(23):12282-93. PMC: 4933276. DOI: 10.1074/jbc.M115.698092. View

Zhao L, Hua T, Crowley C, Ru H, Ni X, Shaw N . Structural analysis of asparaginyl endopeptidase reveals the activation mechanism and a reversible intermediate maturation stage. Cell Res. 2014; 24(3):344-58. PMC: 3945893. DOI: 10.1038/cr.2014.4. View

White C, Yang H, Yu L, Chibnik L, Dawe R, Yang J . Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data. PLoS Med. 2017; 14(4):e1002287. PMC: 5404753. DOI: 10.1371/journal.pmed.1002287. View

10.

Glasgow S, Labrecque S, Beamish I, Aufmkolk S, Gibon J, Han D . Activity-Dependent Netrin-1 Secretion Drives Synaptic Insertion of GluA1-Containing AMPA Receptors in the Hippocampus. Cell Rep. 2018; 25(1):168-182.e6. DOI: 10.1016/j.celrep.2018.09.028. View

11.

Cline M, Juarez B, Hunker A, Regiarto E, Hariadi B, Soden M . Netrin-1 regulates the balance of synaptic glutamate signaling in the adult ventral tegmental area. Elife. 2023; 12. PMC: 10023152. DOI: 10.7554/eLife.83760. View

12.

Ju T, Sun L, Fan Y, Wang T, Liu Y, Liu D . Decreased Netrin-1 in Mild Cognitive Impairment and Alzheimer's Disease Patients. Front Aging Neurosci. 2022; 13:762649. PMC: 8888826. DOI: 10.3389/fnagi.2021.762649. View

13.

Lin L, Rao Y, Isacson O . Netrin-1 and slit-2 regulate and direct neurite growth of ventral midbrain dopaminergic neurons. Mol Cell Neurosci. 2005; 28(3):547-55. DOI: 10.1016/j.mcn.2004.11.009. View

14.

Zhang C, Jin Y, Ziemba K, Fletcher A, Ghosh B, Truit E . Long distance directional growth of dopaminergic axons along pathways of netrin-1 and GDNF. Exp Neurol. 2013; 250:156-64. PMC: 4038353. DOI: 10.1016/j.expneurol.2013.09.022. View

15.

Yang H, Chhatwal J, Xu J, White C, Hanseeuw B, Rabin J . An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults. J Alzheimers Dis. 2019; 68(3):1161-1170. PMC: 6571137. DOI: 10.3233/JAD-180788. View

16.

Kim S, Martin K . Neuron-wide RNA transport combines with netrin-mediated local translation to spatially regulate the synaptic proteome. Elife. 2015; 4. PMC: 4337609. DOI: 10.7554/eLife.04158. View

17.

Singh N, Benoit M, Zhou J, Das B, Davila-Velderrain J, Kellis M . BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1. Sci Adv. 2022; 8(24):eabo1286. PMC: 9205595. DOI: 10.1126/sciadv.abo1286. View

18.

Cord B, Li J, Works M, McConnell S, Palmer T, Hynes M . Characterization of axon guidance cue sensitivity of human embryonic stem cell-derived dopaminergic neurons. Mol Cell Neurosci. 2010; 45(4):324-34. DOI: 10.1016/j.mcn.2010.07.004. View

19.

Li B, Shen K, Zhang J, Jiang Y, Yang T, Sun X . Serum netrin-1 as a biomarker for colorectal cancer detection. Cancer Biomark. 2020; 28(3):391-396. DOI: 10.3233/CBM-190340. View

20.

Osborne P, Halliday G, Cooper H, Keast J . Localization of immunoreactivity for deleted in colorectal cancer (DCC), the receptor for the guidance factor netrin-1, in ventral tier dopamine projection pathways in adult rodents. Neuroscience. 2005; 131(3):671-81. DOI: 10.1016/j.neuroscience.2004.11.043. View