TM2D genes regulate Notch signaling and neuronal function in Drosophila.

Jose L Salazar,G Gregory Neely,Yong Qi Lin,Shinya Yamamoto,Samantha L Deal,Paul C Marcogliese,David Li-Kroeger,Sheng-An Yang,Fengwei Yu

doi:10.1371/journal.pgen.1009962

Jose L Salazar, G Gregory Neely + Show 7 more

Open Access

https://doi.org/10.1371/journal.pgen.1009962

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Abstract

TM2 domain containing (TM2D) proteins are conserved in metazoans and encoded by three separate genes in each model organism species that has been sequenced. Rare variants in TM2D3 are associated with Alzheimer’s disease (AD) and its fly ortholog almondex is required for embryonic Notch signaling. However, the functions of this gene family remain elusive. We knocked-out all three TM2D genes (almondex, CG11103/amaretto, CG10795/biscotti) in Drosophila and found that they share the same maternal-effect neurogenic defect. Triple null animals are not phenotypically worse than single nulls, suggesting these genes function together. Overexpression of the most conserved region of the TM2D proteins acts as a potent inhibitor of Notch signaling at the γ-secretase cleavage step. Lastly, Almondex is detected in the brain and its loss causes shortened lifespan accompanied by progressive motor and electrophysiological defects. The functional links between all three TM2D genes are likely to be evolutionarily conserved, suggesting that this entire gene family may be involved in AD.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the aging population and accounts for the large majority of age-related cases of dementia [1,2]
We investigated the function of TM2D3, a conserved gene that has been implicated in lateonset AD through an exome-wide association study, and two closely related genes, TM2D1 and TM2D2, using the fruit fly Drosophila melanogaster
Together with functional data that implicates TM2D3 in a biological process that is liked to the γ-secretase, a protease that is involved in AD in addition to being required for proper Notch signaling, we propose that all three TM2 domain containing (TM2D) family genes may be involved in AD pathogenesis, which warrants further investigation through human genetics studies

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the aging population and accounts for the large majority of age-related cases of dementia [1,2]. AD is pathologically characterized by histological signs of neurodegeneration that are accompanied by formation of extracellular plaques and intra-neuronal tangles. Rare hereditary forms of AD are caused by dominant pathogenic variants in APP (Amyloid Precursor Protein), PSEN1 (Presenilin 1) or PSEN2 (Presenilin 2). These three genes have been extensively studied using variety of experimental systems, and the resultant knowledge has led to greater understanding of how they contribute to the formation of extracellular plaques found in both familial and sporadic AD brains [4]. PSEN1 and PSEN2 are paralogous genes that encode the catalytic subunit of the γ-secretase, a membrane-bound intramembrane protease complex [5]. PSEN1 and PSEN2 are paralogous genes that encode the catalytic subunit of the γ-secretase, a membrane-bound intramembrane protease complex [5]. γ-secretase substrates include many type-I transmembrane proteins including APP as well as Notch receptors that play various roles in development and physiology [6,7]

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