Axon guidance and synaptic maintenance: preclinical markers for neurodegenerative disease and therapeutics

Abstract

Axon-guidance-pathway molecules are involved in connectivity and repair throughout life (beyond guiding brain wiring during fetal development). One study found that variations (single-nucleotide polymorphisms [SNPs]) in axon-guidance-pathway genes were predictive of three Parkinson's disease (PD) outcomes (susceptibility, survival free of PD and age at onset of PD) in genome-wide association (GWA) datasets. The axon-guidance-pathway genes DCC, EPHB1, NTNG1, SEMA5A and SLIT3 were represented by SNPs predicting PD outcomes. Beyond GWA analyses, we also present relevant neurobiological roles of these axon-guidance-pathway molecules and consider mechanisms by which abnormal axon-guidance-molecule signaling can cause loss of connectivity and, ultimately, PD. Novel drugs and treatments could emerge from this new understanding.

A Commentary on Axon guidance pathway genes and Parkinson’s disease

“…The five mapped axon guidance pathway genes-deleted in colorectal carcinoma (DCC), ephrin receptor B1 (EPHB1), netrin-G1 (NTNG1), semaphorin 5A (SEMA5A) and SLIT3-were found to have SNPs associated with the prediction of PD outcomes (susceptibility, survival free of PD and age at onset of PD). 3,4 Especially, SEMA5A had significant association with PD, suggesting a possible role for axon guidance in the pathogenesis of PD, such as early neurodegeneration in the subclinical period and possibly even during brain development (the miswiring hypothesis). 3,4 Functionally, the axon guidance pathway consists of four major classes of ligands (ephrin, netrin, semaphorin and slit proteins), their respective receptors (for example, eph, DCC and unc, neuropilin and plexin and robo proteins) and several downstream signaling proteins.…”

“…3,4 Especially, SEMA5A had significant association with PD, suggesting a possible role for axon guidance in the pathogenesis of PD, such as early neurodegeneration in the subclinical period and possibly even during brain development (the miswiring hypothesis). 3,4 Functionally, the axon guidance pathway consists of four major classes of ligands (ephrin, netrin, semaphorin and slit proteins), their respective receptors (for example, eph, DCC and unc, neuropilin and plexin and robo proteins) and several downstream signaling proteins. 4 DCC-deficient adult mice showed altered dopamine transmission and locomotor activity accompanied by reduced dendritic spine density in the cerebral cortex.…”

“…3,4 Functionally, the axon guidance pathway consists of four major classes of ligands (ephrin, netrin, semaphorin and slit proteins), their respective receptors (for example, eph, DCC and unc, neuropilin and plexin and robo proteins) and several downstream signaling proteins. 4 DCC-deficient adult mice showed altered dopamine transmission and locomotor activity accompanied by reduced dendritic spine density in the cerebral cortex. 5 These findings show that DCC is a crucial molecule in the development of dopamine circuitry, and alterations in DCC levels can lead to cognitive and behavioral abnormalities in adulthood.…”

“…5 These findings show that DCC is a crucial molecule in the development of dopamine circuitry, and alterations in DCC levels can lead to cognitive and behavioral abnormalities in adulthood. 4,5 In EPHB1-knockout mice, there is a significant cell loss in the substance nigra pars reticulata, but there is no obvious change in the number of dopamine neurons in the substance nigra pars compacta. 6 Differential expression of NTNG1 could alter dopaminergic and glutamatergic circuitry.…”

“…6 Differential expression of NTNG1 could alter dopaminergic and glutamatergic circuitry. 4 SEMA5A could be involved in increasing the risk of PD by causing synaptic activity dysfunction and inflammation. 4 Concerning SLIT3, Slit3/robo pathway is thought to initiate and accelerate the processes or progression of PD.…”