Yu, Y., Niccoli, T., Ren, Z., Woodling, N. S. , Aleyakpo, B., Szabadkai, G. and Partridge, L. (2020) PICALM rescues glutamatergic neurotransmission, behavioural function and survival in a Drosophila model of Aβ42 toxicity. Human Molecular Genetics, 29(14), pp. 2420-2434. (doi: 10.1093/hmg/ddaa125) (PMID:32592479) (PMCID:PMC7424762)
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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 turnover, 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 the accumulation of presynaptic 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 localization of amphiphysin (Amph), the homologue of another AD risk factor BIN1, and that Amph itself modulated postsynaptic glutamate receptor (GluRII) localization. We propose a model where PICALM modulates glutamatergic transmission, together with BIN1, to ameliorate synaptic dysfunction and disease progression.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Woodling, Dr Nathan |
| Authors: | Yu, Y., Niccoli, T., Ren, Z., Woodling, N. S., Aleyakpo, B., Szabadkai, G., and Partridge, L. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Human Molecular Genetics |
| Publisher: | Oxford University Press |
| ISSN: | 0964-6906 |
| ISSN (Online): | 1460-2083 |
| Copyright Holders: | Copyright: © The Author(s) 2020 |
| First Published: | First published in Human Molecular Genetics 29(14): 2420-2434 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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