V232M substitution restricts a distinct O-glycosylation of PLD3 and its neuroprotective function

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• The role of the phospholipase D3 (PLD3) Val232Met variant in late-onset Alzheimer's disease (AD) remains unclear.
• PLD3 may influence cellular compartments beyond direct amyloid precursor protein interaction.

Purpose of the Study:

• Investigate the function of wild-type PLD3 (PLD3^WT) and the Val232Met variant (PLD3^VM) in a Drosophila melanogaster model of AD.
• Assess the impact of PLD3 variants on endoplasmic reticulum (ER) stress, neuronal apoptosis, and cognitive function in the presence of β-amyloid (Aβ).

Main Methods:

• Expression of PLD3^WT and PLD3^VM in the central nervous system (CNS) of an Aβ-induced Drosophila AD model.
• Monitoring ER stress, apoptosis, antioxidative phospholipid levels, and cognitive recovery.
• Analysis of PLD3 O-glycosylation, cellular trafficking, and lysosomal function.

Main Results:

• PLD3^WT expression reduced ER stress and neuronal apoptosis, normalizing phospholipid levels and protecting the brain.
• The V232M substitution disrupts O-glycosylation at pT271, impairing PLD3 trafficking to lysosomes, causing lysosomal enlargement, and aberrant protein recycling.
• PLD3^VM exhibited reduced neuroprotective effects compared to PLD3^WT, which enhanced lysosomal function.

Conclusions:

• The PLD3 Val232Met variant may contribute to AD pathogenesis through impaired lysosomal trafficking and protein recycling.
• PLD3's mechanistic role in AD warrants further investigation for potential therapeutic target development.