Molecular deciphering of disease processes in SLC12A6-associated sensorimotor neuropathy

Abstract-Text (inkl. Referenzen)

Introduction: Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Recessive variants in SLC12A6 cause hereditary motor and sensory neuropathy with agenesis of the corpus callosum and dominant variants axonal CMT type 2II. Although SLC12A6 (KCC3) mediates electroneutral potassium-chloride cotransport, related disease processes are incompletely understood.

Methods: To unravel molecular disease processes associated with a dominant SLC12A6-variant (p.Tyr679Cys), we performed proteomics, metabolomics, functional and microscopic studies on patient-derived fibroblasts. To focus on mitochondrial capabilities, cells were treated with nicotinamide riboside (NR).

Results: We identified changes in the proteomic and metabolomic signature of patient-derived cells which are in line with altered mitochondrial activity as identified by functional studies. Over 50 metabolites from amino acids, purine and TCA cycle pathways were altered in patient fibroblasts also influenced by NR-treatment.

Discussion: Our findings expand the current knowledge on the molecular etiology of axonal CMT type 2II, strengthen our understanding of peripheral nerve vulnerability and provide further insights into the activation of potential compensatory mechanisms for instance by increase of inosine, guanosine, and cytidine. Combined results accord with altered mitochondrial activity.