Pathway Analyses of Inherited Neuropathies Identify Putative Common Mechanisms of Axon Degeneration.

Abstract

Objective: Inherited neuropathies (IN) are associated with over 100 different genetic mutations presenting with a variety of phenotypes. This complexity suggests multiple pathways may converge onto a limited number of downstream pathways to effect axonal injury. Ontologic and protein-protein interaction (PPI) studies of the genes associated with inherited disorders of axon degeneration can identify these putative pathophysiologic mechanisms. Comparison with pathways in central disorders of axon degeneration may reveal universal pathways and, thus, therapeutic targets.

Methods: Pathway analyses of genes associated with IN with axonal, demyelinating, and intermediate phenotypes and hereditary spastic paraplegia (HSP) were performed using the Metascape resource. The resulting PPI and ontology networks were analyzed for common and shared versus disparate pathways. Pathways from IN were also compared to those of HSP.

Results: PPI networks demonstrated robust integration of the phenotype-specific networks, with over 20 hubs identified and highly interconnected networks of tRNA aminoacylation and intracellular trafficking. The voltage-gated sodium channel-associated axonal IN did not integrate with the rest of the network, prefiguring potentially different pathophysiologic processes. Ontologic analyses identified tRNA metabolism, axonal transport, and endomembrane/organelle trafficking to be common to all IN phenotypes. There was overlap of these IN ontologic processes with those identified in HSP, suggestive of common pathways involved in the development of inherited, length-dependent axonopathies.

Interpretation: Intracellular trafficking and endomembrane/organelle transport are common pathways associated with inherited axonopathies. Therapies targeting tRNA metabolism and intracellular trafficking are promising therapeutic targets given the convergent PPIs of these subnetworks.