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

Abstract

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 < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K v 4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6 , as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate. Electronic supplementary material The online version of this article (10.1007/s00401-019-01976-3) contains supplementary material, which is available to authorized users.

Activity-dependent isomerization of Kv4.2 by Pin1 regulates cognitive flexibility

“…The p38 MAPK pathway is possible target for the treatment a number of neurodegenerative diseases, such as AD 59 . Thus, this Kv4.2 phosphorylation-Pin1 mechanism could be applied to treat pathological conditions and neurodegeneration diseases 22 .…”

“…Cognitive inflexibility is observed in various psychiatric disorders such as autism spectrum disorder (ASD) 65 , schizophrenia 66 , suicidal ideation 67 , and anxiety and mood disorders 68 . Considering that both Kv4.2 and DPP6 are implicated in such psychiatric disorders 8,22,69 , the stability of the Kv4.2-DPP6 complex might be a common factor of pathophysiology. It will be interesting to examine if the T607A mutation can rescue cognitive inflexibility in mouse models of psychiatric or neurodegenerative disorders.…”

“…18 ). Recent studies have identified DPP6 and DPP10 as genes associated with autism 19 , amyotrophic lateral sclerosis 20,21 and neurodegeneration 22 . Thus, the regulation of the Kv4.2-DPP6 complex may not only affect Kv4.2 channel activity but also influence Kv4.2-independent functions of DPP6.…”

Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export

“…The PD cohort consisted of 617 unrelated patients (mean age at onset (AAO) 60.0 ± 11.5 years, 31.8% women, 18.6% with a positive familial history) and the DLB cohort consisted of 226 unrelated patients (mean AAO 70.8 ± 9.8 years; 32.7% female, 23.0% with a positive familial history) recruited in the framework of the Belgian Neurology (BELNEU) Consortium, a multicenter collaboration of neurology expertise centers in Belgium [20,41]. Index patients were evaluated with a detailed clinical history of patients and family, clinical neurological examination, and neuroimaging.…”

Novel Alzheimer’s disease risk genes: exhaustive investigation is paramount

“…[5]). Corroborated by both earlier and more recent evidence in different loci [7,8], these findings illustrate that the repertoire of genetic variation to be investigated as risk factors for AD should be broadened. Technologies such as long-read sequencing will facilitate this in the years to come.…”