Intracellular Calcium Deficits in Drosophila Cholinergic Neurons Expressing Wild Type or FAD-Mutant Presenilin

Kinga Michno,Jorge M Campussano,David Knight,Gabrielle L Boulianne,Diana Van De Hoef,David C Rubinsztein

doi:10.1371/journal.pone.0006904

Abstract

Much of our current understanding about neurodegenerative diseases can be attributed to the study of inherited forms of these disorders. For example, mutations in the presenilin 1 and 2 genes have been linked to early onset familial forms of Alzheimer's disease (FAD). Using the Drosophila central nervous system as a model we have investigated the role of presenilin in one of the earliest cellular defects associated with Alzheimer's disease, intracellular calcium deregulation. We show that expression of either wild type or FAD-mutant presenilin in Drosophila CNS neurons has no impact on resting calcium levels but does give rise to deficits in intracellular calcium stores. Furthermore, we show that a loss-of-function mutation in calmodulin, a key regulator of intracellular calcium, can suppress presenilin-induced deficits in calcium stores. Our data support a model whereby presenilin plays a role in regulating intracellular calcium stores and demonstrate that Drosophila can be used to study the link between presenilin and calcium deregulation.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized clinically by progressive dementia and histopathologically by the formation of neuritic plaques, neurofibrillary tangles (NFT) and neuronal cell death
In this study we have investigated the impact of wild type and mutant presenilin expression on intracellular calcium dynamics in primary Drosophila cholinergic neurons
presenilin gene (Psn)-induces deficits in intracellular calcium stores To investigate the effect of Psn expression on intracellular calcium dynamics in a cell type relevant to AD, we chose to focus on cholinergic central nervous system (CNS) neurons, as their loss is a prominent feature in AD brains [37]

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized clinically by progressive dementia and histopathologically by the formation of neuritic plaques, neurofibrillary tangles (NFT) and neuronal cell death. 50% of FAD cases have been attributed to mutations in three genes, amyloid precursor protein (APP) [1], presenilin-1 (PSEN1) [2] or presenilin-2 (PSEN2) [3]. In the ER, presenilins undergo proteolytic cleavage generating N- and Cterminal fragments, which remain associated. Presenilins associate with presenilin enhancer-2, nicastrin and anterior pharynx defective-1. Together these proteins constitute the c-secretase complex. APP proteolysis is important to AD because aberrant APP proteolysis results in the deposition of Ab fragments, which are the primary components of neuritic plaques.

Methods

Results

Conclusion