Whole-exome sequencing has identified rare coding variants in the phospholipase D3 (PLD3) gene as associated with increased risk for late-onset Alzheimer disease. (However, see discussion in MIM:615711.) There is a high-scoring ortholog of PLD3 in Drosophila, Dmel\Pld3, for which RNAi-targeting constructs have been generated. Dmel\Pld3 is also orthologous to human PLD4 and PLD5. Human PLD3 is also implicated in a form of spinocerebellar ataxia (MIM:617770).
Using a fly model of Alzheimer disease 1 (FBhh0000119; Aβ42 model with the Artic variant), the impact of wild-type human Hsap\PLD3 vs. an implicated variant form (Val232Met) of the human gene has been assessed. Both the wild-type and variant forms of Hsap\PLD3 reduce the neurodegenerative, cognitive, and cellular phenotypes observed in the Alzheimer disease model, but the variant form shows a significantly weaker protective effect across multiple different phenotypic assays. Variant(s) implicated in human disease tested (as transgenic human gene, PLD3): the V232M variant form has been introduced into flies. It is postulated that this variant form impairs O-glycosylation of PLD3, which is necessary for its normal trafficking and cellular localization.
Knockdown of Dmel\Pld3, effected by RNAi, dramatically exacerbates the reduced lifespan phenotype observed for the Alzheimer disease fly model ((FBhh0000119; Aβ42 model with the Artic variant).
[updated Mar. 2021 by FlyBase; FBrf0222196]
Alzheimer disease (AD) is the most common form of progressive dementia in the elderly. [from MIM:104300; 2016.01.08]
Memory loss is the most common sign of Alzheimer disease. As the disorder progresses, some people with AD experience personality and behavioral changes; other common symptoms include agitation, restlessness, withdrawal, and loss of language skills. Total care is usually required during the advanced stages of the disease. Affected individuals usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Death usually results from pneumonia, malnutrition, or general body wasting. [from Genetics Home Reference, Alzheimer disease; 2016.01.08]
Alzheimer disease can be classified as early-onset or late-onset. The signs and symptoms of the early-onset form appear before age 65, while the late-onset form appears after age 65. The early-onset form is much less common than the late-onset form, accounting for less than 5 percent of all cases of Alzheimer disease. [from Genetics Home Reference, Alzheimer disease; 2016.01.08]
Whole-exome sequencing has associated rare coding variants in the phospholipase D3 (PLD3) gene with increased risk for late-onset Alzheimer disease; variants with significant association with Alzheimer's disease risk include Met6Arg and Val232Met (Wang et al., 2014; pubmed:24935720).
PLD3 encodes a member of the phospholipase D (PLD) family of enzymes that catalyze the hydrolysis of membrane phospholipids. The PLD3 protein is a single-pass type II membrane protein and contains two PLD phosphodiesterase domains; it may be involved in APP (amyloid beta precursor protein) processing. [Gene Cards, PLD3; 2019.12.17]
The PLD3 gene is expressed at higher levels in the brain, especially in neurons, than in non-nervous tissues (Wang et al., 2014; pubmed:24935720).
Many to many: 3 human to 2 Drosophila. The human genes are PLD3, PLD4, and PLD5.
High-scoring ortholog of human PLD3; moderate-scoring ortholog of PLD4 and PLD5 (2 Drosophila to 3 human). Dmel\Pld3 shares 49% identity and 63% similarity with the human PLD3 gene.
