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PLoS One. 2018 Aug 7;13(8):e0200988. doi: 10.1371/journal.pone.0200988. eCollection 2018.

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

Author information

1
Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
2
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
3
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama, Japan.
4
Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science, Kyoto, Japan.
5
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.

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.

PMID:
30086173
PMCID:
PMC6080755
DOI:
10.1371/journal.pone.0200988
[Indexed for MEDLINE]
Free PMC Article

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