Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila

Area of Science:

• Neurogenetics
• Molecular Biology
• Biochemistry

Background:

• Mutations in patatin-like phospholipase domain-containing protein 6 (PNPLA6) are associated with inherited neurological disorders.
• PNPLA6, an evolutionary conserved phospholipase, hydrolyzes lysophosphatidylcholine (LPC) and phosphatidylcholine (PC).
• Loss of PNPLA6 function leads to increased lipid levels, locomotion deficits, and neurodegeneration.

Purpose of the Study:

• To investigate the in vivo functional consequences of different PNPLA6 mutations.
• To determine if disease-associated PNPLA6 mutations retain biological activity.
• To explore the role of cNMP binding sites in PNPLA6 regulation.

Main Methods:

• Expressed human wild-type and mutant PNPLA6 in Drosophila sws null mutant flies.
• Assessed suppression of locomotion and neurodegenerative phenotypes.
• Measured restoration of lipid levels (LPC and PC).

Main Results:

• Wild-type human PNPLA6 rescued Drosophila sws mutant phenotypes and restored normal lipid levels.
• Mutant PNPLA6 proteins suppressed behavioral and degenerative phenotypes but did not restore lipid levels.
• Mutations in cNMP binding sites impaired lipid level restoration, supporting cNMP regulation of PNPLA6 activity.

Conclusions:

• Disease-associated PNPLA6 mutants retain partial biological function beyond lipid homeostasis disruption.
• Lipid homeostasis disruption is a significant but not the sole pathogenic mechanism in PNPLA6-related disorders.
• cNMP binding sites are critical for PNPLA6 phospholipase activity and regulation.