Dysfunction of the Endosomal Na+/H+ Exchanger 6 (NHE6) in Cellular Models of Corticobasal Syndrome

Abstract

Corticobasal syndrome (CBS) is a neurodegenerative disease with the main symptoms including parkinsonism and frontotemporal dementia. The most common pathology underlying the disease is corticobasal degeneration (CBD), where hyperphosphorylated forms of the microtubule-associated protein tau accumulate. A common occurance in many neurodegenerative diseases is a dysfunction of the endosomal-lysosomal system including defects in receptor recycling and autophagic removal of defective organelles. In 2013, Riess et al. identified a mutation in the SLC9A6 gene coding for the endosomal cation exchanger 6 (NHE6) in a family with rare X-linked mental retardation in male members of the family. The grandmother of the index patient was subsequently shown to suffer from CBS and the work presented in the talk investigated the consequences of a loss of NHE6 in cellular models of the disease. NHE6 is involved in the regulating of the pH of the endosomal-lysosomal system. In line with this, an impairment of NHE6 function caused hyper-acidification across the endosomal-lysosomal system, affected endosomal maturation and led to impairments in autophagy. Using an inducible knockdown model in neuronal cancer cells, an increase in the phosphorylation of tau could be shown, and insoluble tau accumulated differently in brain tissue obtained from CBS patients with a variant in the SLC9A6 gene. In summary, NHE6 loss of function deregulates endosomal-lysosomal pH, impacts the endosomal-lysosomal system, autophagy and tau status, and could prove a valuable target for study in CBS and other tau-related neurodegenerative diseases.