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

ABSTRACT: Although the aggregation of amyloid-? peptide (A?) clearly plays a central role in the pathogenesis of Alzheimer's disease (AD), endosomal traffic dysfunction is considered to precede A? aggregation and trigger AD pathogenesis. A body of evidence suggests that the ?-carboxyl-terminal fragment (?CTF) of amyloid-? precursor protein (APP), which is the direct precursor of A?, 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 ?CTF. 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 ?CTF 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 ?CTF. In addition, we found that expressed BACE1 accumulated in enlarged endosomes and increased A? production. Our data suggested that TMEM30A is involved in ?CTF-dependent endosome abnormalities that are related to A? overproduction.

SUBMITTER: Takasugi N 

PROVIDER: S-EPMC6080755 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Takasugi Nobumasa N   Araya Runa R   Kamikubo Yuji Y   Kaneshiro Nanaka N   Imaoka Ryosuke R   Jin Hao H   Kashiyama Taku T   Hashimoto Yoshie Y   Kurosawa Masaru M   Uehara Takashi T   Nukina Nobuyuki N   Sakurai Takashi T  

PloS one 20180807 8

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  ...[more]

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