Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene ( DPP6 ). DPP6 resequencing identified significantly more rare variants—nonsense, frameshift, and missense—in early-onset Alzheimer’s disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05–4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28–5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K v 4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression ( p