TMEM30A is a candidate interacting partner for the β-carboxyl-terminal fragment of amyloid-β precursor protein in endosomes.

Nobumasa Takasugi,Takashi Uehara,Ryosuke Imaoka,Nanaka Kaneshiro,Yoshie Hashimoto,Hao Jin,Taku Kashiyama,Yuji Kamikubo,Nobuyuki Nukina,Masaru Kurosawa,Runa Araya,Takashi Sakurai,Madepalli K Lakshmana

doi:10.1371/journal.pone.0200988

Abstract

Although the aggregation of amyloid-β peptide (Aβ) clearly plays a central role in the pathogenesis of Alzheimer’s disease (AD), endosomal traffic dysfunction is considered to precede Aβ aggregation and trigger AD pathogenesis. A body of evidence suggests that the β-carboxyl-terminal fragment (βCTF) of amyloid-β precursor protein (APP), which is the direct precursor of Aβ, accumulates in endosomes and causes vesicular traffic impairment. However, the mechanism underlying this impairment remains unclear. Here we identified TMEM30A as a candidate partner for βCTF. TMEM30A is a subcomponent of lipid flippase that translocates phospholipids from the outer to the inner leaflet of the lipid bilayer. TMEM30A physically interacts with βCTF in endosomes and may impair vesicular traffic, leading to abnormally enlarged endosomes. APP traffic is also concomitantly impaired, resulting in the accumulation of APP-CTFs, including βCTF. In addition, we found that expressed BACE1 accumulated in enlarged endosomes and increased Aβ production. Our data suggested that TMEM30A is involved in βCTF-dependent endosome abnormalities that are related to Aβ overproduction.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by senile plaques and neurofibrillary tangles
Morphometric comparison revealed that cotransfection with TMEM30A enlarged Aβ precursor protein (APP)-containing vesicles to >0.8 μm2, which was rarely observed in singly transfected cells (Fig 1B)
The interaction between TMEM30A and full length APP (FL-APP)/β-carboxyl-terminal fragment (βCTF) may have induced abnormally enlarged endosomes, which accumulated the early endosome marker Rab5 (Fig 1A–1C), late endosome marker Rab7, and recycling endosome marker Rab11 (Fig 7A and 7B). These results are similar to the accumulation of various Rab markers in enlarged endosomes that have been observed in the brains of aged monkeys [6], as well as in the brains of patients with AD and Down syndrome (DS) [5, 35]

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by senile plaques and neurofibrillary tangles. Amyloid-β (Aβ), the major component of senile plaques, is produced from the sequential cleavage of Aβ precursor protein (APP) by β-site APPcleaving enzyme 1 (BACE1) and γ-secretase [1]. Go.jp), a Grant-in-Aid of The Fugaku Trust for Medicinal Research (TS) and Life Science Foundation of Japan The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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Conclusion