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

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.