Abstract
IntroductionRecently, a whole-exome sequencing (WES) study showed that a rare variant rs145999145 composed of p.Val232Met located in exon 7 of the phospholipase D3 (PLD3) gene confers a doubled risk for late-onset Alzheimer’s disease (AD). Knockdown of PLD3 elevates the levels of extracellular amyloid-beta (Aβ), suggesting that PLD3 acts as a negative regulator of Aβ precursor protein (APP) processing. However, the precise cellular location and distribution of PLD3 in AD brains remain largely unknown.MethodsBy quantitative RT-PCR (qPCR), western blot, immunohistochemistry, and bioinformatics analysis, we studied PLD3 expression patterns and levels in a series of AD and control brains, including amyotrophic lateral sclerosis, Parkinson’s disease, multiple system atrophy, and non-neurological cases.ResultsThe levels of PLD3 mRNA and protein expression were reduced modestly in AD brains, compared with those in non-AD brains. In all brains, PLD3 was expressed constitutively in cortical neurons, hippocampal pyramidal and granular neurons but not in glial cells. Notably, PLD3 immunoreactivity was accumulated on neuritic plaques in AD brains. We identified the human granulin (GRN) gene encoding progranulin (PRGN) as one of most significant genes coexpressed with PLD3 by bioinformatics database search. PLD3 was actually coexpressed and interacted with PGRN both in cultured cells in vitro and in AD brains in vivo.ConclusionsWe identified an intense accumulation of PLD3 on neuritic plaques coexpressed with PGRN in AD brains, suggesting that PLD3 plays a key role in the pathological processes of AD.
Highlights
A whole-exome sequencing (WES) study showed that a rare variant rs145999145 composed of p.Val232Met located in exon 7 of the phospholipase D3 (PLD3) gene confers a doubled risk for late-onset Alzheimer’s disease (AD)
Whole-exome sequencing studies discovered rare functional variants located in amyloid beta (Aβ) precursor protein (APP), triggering receptor expressed on myeloid cells 2 (TREM2), and phospholipase D3 (PLD3) genes that exhibit a much greater contribution to protection or development of AD [3,4,5]
By searching the genes coexpressed with PLD3 on COXPRESdb [23], we identified the human GRN gene encoding PGRN, whose mutation is responsible for frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis [24], ranked as the second most significant gene coexpressed with PLD3 (Additional file 6)
Summary
A whole-exome sequencing (WES) study showed that a rare variant rs145999145 composed of p.Val232Met located in exon 7 of the phospholipase D3 (PLD3) gene confers a doubled risk for late-onset Alzheimer’s disease (AD). Whole-exome sequencing studies discovered rare functional variants located in Aβ precursor protein (APP), triggering receptor expressed on myeloid cells 2 (TREM2), and phospholipase D3 (PLD3) genes that exhibit a much greater contribution to protection or development of AD [3,4,5]. Phospholipase D (PLD), a phospholipid-modifying enzyme whose activation is triggered by growth factors, hormones, and neurotransmitters, catalyzes the hydrolysis of phosphatidylcholine to generate free choline and phosphatidic acid, the latter of which is converted into diacylglycerol by phosphatidic acid phosphatases [6,7] Both phosphatidic acid and diacylglycerol, by acting as a second messenger, play a key role in membrane trafficking, cytoskeleton reorganization, receptor-mediated endocytosis, exocytosis, cell growth, differentiation, migration, and regulation of the cell cycle. PLD is directly activated by phosphatidylinositol 4,5-bisphosphate, ADPribosylation factor, Rho family small GTPases, and protein kinase C [6,7]
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