Mutations of Presenilin Genes in Dilated Cardiomyopathy and Heart Failure

Abstract

Two common disorders of the elderly are heart failure and Alzheimer disease (AD). Heart failure usually results from dilated cardiomyopathy (DCM). DCM of unknown cause in families has recently been shown to result from genetic disease, highlighting newly discovered disease mechanisms. AD is the most frequent neurodegenerative disease of older Americans. Familial AD is caused most commonly by presenilin 1 (PSEN1) or presenilin 2 (PSEN2) mutations, a discovery that has greatly advanced the field. The presenilins are also expressed in the heart and are critical to cardiac development. We hypothesized that mutations in presenilins may also be associated with DCM and that their discovery could provide new insight into the pathogenesis of DCM and heart failure. A total of 315 index patients with DCM were evaluated for sequence variation in PSEN1 and PSEN2. Families positive for mutations underwent additional clinical, genetic, and functional studies. A novel PSEN1 missense mutation (Asp333Gly) was identified in one family, and a single PSEN2 missense mutation (Ser130Leu) was found in two other families. Both mutations segregated with DCM and heart failure. The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death. The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis. Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers. These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart failure and implicate novel mechanisms of myocardial disease.

Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

“…Because CA1 neurons in 3×TgAD mice exhibit accumulation of Aβ oligomers and hyperphosphorylated tau, whereas CA1 neurons in PS1KI mice do not (Guo et al, 1999;Oddo et al, 2003Billings et al, 2005), our findings suggest that the adverse effects of PS1 mutations on cholinergic and NMDA-mediated synaptic plasticity are independent of Aβ and tau pathologies. Indeed, families have recently been identified in which PS1 mutations cause frontotemporal dementia [48] (Zekanowski et al, 2006) or cardiomyopathy and heart failure (Li et al, 2006), disorders that lack amyloid pathology. The mechanisms identified in the present study may explain the increased Ca 2+ responses and increased afterhyperpolarization of hippocampal neurons (Barrow et al, 2000) and the defective associative learning (Wang et al, 2004a) previously documented in studies of presenilin mutant mice.…”

Proteostasis in cardiac health and disease

“…This connec tion seems to be primarily explained by vascular risk factors affecting both conditions, including the genetic polymorphism best predicting Alzheimer disease, the apolipoprotein E4 isoform. Nevertheless, screening of patients with DCM revealed mutations in the genes encoding presenilin 1 and presenilin 2 -proteins implicated in familial (early onset) Alzheimer disease that are also expressed in the heart 126 . A potential role for presenilins in cardiac disease in familial Alzheimer disease is also suggested by phenotypes of presenilin deficient mice.…”

Pathogenic Angiogenic Mechanisms in Alzheimer's Disease

“…It is also seen that the presenilins are expressed in the heart and are critical to cardiac development. The work by Li et al indicated that PSEN1 and PSEN2 mutations are associated with dilated cardiomyopathy (DCM) and heart failure and implicate novel mechanisms of myocardial disease [15]. Amyloid is a known vasculotrope and an increased amyloid aggregation in AD brains is seen to be in interaction with the angiogenic and CAA positive vessels [14].…”

“…Carriers of this isoform show a decreased cerebral blood flow and have also been linked to disorders associated with elevated cholesterol levels or lipid derangements (i.e. hyperlipoproteinemia type III, coronary heart disease, strokes, peripheral artery disease and diabetes mellitus) [15]. These overlapping genetic risk factors might give us a direction for understanding the mechanisms of the disease-related pathways.…”