UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

PICALM rescues glutamatergic neurotransmission, behavioural function, and survival in a Drosophila model of Aβ42 toxicity

Yu, Y; Niccoli, T; Ren, Z; Woodling, NS; Aleyakpo, B; Szabadkai, G; Partridge, L; (2020) PICALM rescues glutamatergic neurotransmission, behavioural function, and survival in a Drosophila model of Aβ42 toxicity. Human Molecular Genetics 10.1093/hmg/ddaa125. (In press). Green open access

[thumbnail of ddaa125.pdf]
Preview
Text
ddaa125.pdf - Accepted Version

Download (2MB) | Preview

Abstract

Alzheimer's disease (AD) is the most common form of dementia and the most prevalent neurodegenerative disease. Genome Wide Association Studies have linked PICALM to AD risk. PICALM has been implicated in Aβ42 production and turn-over, but whether it plays a direct role in modulating Aβ42 toxicity remains unclear. We found that increased expression of the Drosophila PICALM orthologue lap could rescue Aβ42 toxicity in an adult-onset model of AD, without affecting Aβ42 level. Imbalances in the glutamatergic system, leading to excessive, toxic stimulation have been associated with AD. We found that Aβ42 caused accumulation of pre-synaptic vesicular glutamate transporter (VGlut) and increased spontaneous glutamate release. Increased lap expression reversed these phenotypes back to control levels, suggesting that lap may modulate glutamatergic transmission. We also found that lap modulated the localisation of Amph, the homologue of another AD risk factor BIN1, and that Amph itself modulated post-synaptic glutamate receptor (GluRII) localisation. We propose a model where PICALM modulates glutamatergic transmission, together with BIN1, to ameliorate synaptic dysfunction and disease progression.

Type: Article
Title: PICALM rescues glutamatergic neurotransmission, behavioural function, and survival in a Drosophila model of Aβ42 toxicity
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddaa125
Publisher version: https://doi.org/10.1093/hmg/ddaa125
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/10105480
Downloads since deposit
28Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item