Abstract
Mutations in patatin-like phospholipase domain-containing protein 6 (PNPLA6) have been linked with a number of inherited diseases with clinical symptoms that include spastic paraplegia, ataxia, and chorioretinal dystrophy. PNPLA6 is an evolutionary conserved protein whose ortholog in Drosophila is Swiss-Cheese (SWS). Both proteins are phospholipases hydrolyzing lysophosphatidylcholine (LPC) and phosphatidylcholine (PC). Consequently, loss of SWS/PNPLA6 in flies and mice increases both lipids and leads to locomotion deficits and neurodegeneration. PNPLA6 knock-out mice are embryonic lethal, and a mutation creating an early stop codon in human PNPLA6 has only been identified in compound heterozygote patients. In contrast, disease-causing point mutations are found in homozygous patients, with some localized in the phospholipase domain while others are in a region that contains several cNMP binding sites. To investigate how different mutations affect the function of PNPLA6 in an in vivo model, we expressed them in the Drosophila sws1 null mutant. Expressing wild-type PNPLA6 suppressed the locomotion and degenerative phenotypes in sws1 and restored lipid levels, confirming that the human protein can replace fly SWS. In contrast, none of the mutant proteins restored lipid levels, although they suppressed the behavioral and degenerative phenotypes, at least in early stages. These results show that these mutant forms of PNPLA6 retain some biological function, indicating that disruption of lipid homeostasis is only part of the pathogenic mechanism. Furthermore, our finding that mutations in the cNMP binding sites prevented the restoration of normal lipid levels supports previous evidence that cNMP regulates the phospholipase activity of PNPLA6.
Highlights
Hereditary spastic paraplegias (HSPs) are inherited degenerative disorders that mainly affect motor neurons, leading to progressive spasticity and weakness of the lower extremities (Fink, 2013; de Souza et al, 2017; Parodi et al, 2017; Blackstone, 2018)
PNPLA6-Related Diseases in Drosophila linked with Boucher–Neuhäuser, Gordon–Holmes, Laurence– Moon, and Oliver–McFarlane Syndrome, complex diseases with varying clinical symptoms that include hypogonadism, chorioretinal dystrophy, ataxia, spasticity, and, less frequently, peripheral neuropathy and impaired cognitive functions (Deik et al, 2014; Synofzik et al, 2014; Topaloglu et al, 2014; Kmoch et al, 2015)
PNPLA6 belongs to a family of hydrolases with at least eight members in mammals that react with different substrates such as phospholipids, triacylglycerols, and retinol esters (Kienesberger et al, 2009)
Summary
Hereditary spastic paraplegias (HSPs) are inherited degenerative disorders that mainly affect motor neurons, leading to progressive spasticity and weakness of the lower extremities (Fink, 2013; de Souza et al, 2017; Parodi et al, 2017; Blackstone, 2018). Knocking out PNPLA6 in glia resulted in incomplete ensheathment of Remak fibers by non-myelinating Schwann cells in adult sciatic nerves (McFerrin et al, 2017) In agreement with these phenotypes, PNPLA6 is expressed in Schwann cells in the peripheral nervous system starting around post-natal day 5 (McFerrin et al, 2017). For SWS, it has been shown that the latter is required for binding to the C3 catalytic domain of PKA (PKA-C3), whereby SWS inhibits the activity of PKA-C3 (Bettencourt da Cruz et al, 2008) These similarities indicate that SWS and PNPLA6 are both structurally and functionally conserved, which we confirmed by demonstrating that expression of either mouse or human PNPLA6 restored SWS function in Drosophila (Muhlig-Versen et al, 2005; Topaloglu et al, 2014). We have used the fly SWS model to investigate the consequences that different disease-associated PNPLA6 mutations have on the functions of this protein
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