TM2D genes regulate Notch signaling and neuronal function in Drosophila

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• TM2D proteins are conserved across metazoans, encoded by three genes per species.
• Rare TM2D3 variants are associated with Alzheimer's disease (AD).
• The function of the TM2D gene family remains largely unknown.

Purpose of the Study:

• To investigate the function of the TM2D gene family.
• To explore the role of TM2D genes in neurogenesis and potential links to AD.

Main Methods:

• Knockout of all three TM2D genes (almondex, amaretto, biscotti) in Drosophila.
• Analysis of neurogenic defects in knockout flies.
• Overexpression studies of conserved TM2D protein regions.
• Assessment of lifespan, motor function, and electrophysiology in Almondex-deficient flies.

Main Results:

• All three TM2D genes share a maternal-effect neurogenic defect in Drosophila.
• Triple null mutants showed no enhanced phenotype compared to single mutants, indicating functional redundancy.
• Overexpression of TM2D proteins inhibits Notch signaling at the gamma-secretase cleavage step.
• Almondex is present in the brain; its loss leads to reduced lifespan and progressive motor/electrophysiological deficits.

Conclusions:

• The TM2D gene family acts redundantly and is crucial for neurogenesis.
• TM2D proteins likely inhibit Notch signaling via gamma-secretase.
• The conserved functions of TM2D genes suggest a potential role in Alzheimer's disease pathogenesis.