Absence of Sac2/INPP5F enhances the phenotype of a Parkinson’s disease mutation of synaptojanin 1
Mian Cao, Daehun Park, Yumei Wu, Pietro De Camilli
Abstract
Significance Extensive genetic studies have identified numerous genes whose mutations results on Parkinson’s disease (PD), including synaptojanin 1 (SJ1/Park20), a nerve terminal enriched protein that includes an inositol 4-phosphatase domain (Sac domain). In addition, many PD candidate genes have been identified by genome-wide association studies, but for most of these genes, the link to PD remains hypothetical. One such gene is Sac2/INPP5F, which, interestingly, also includes an inositol 4-phosphatase domain. While Sac2KO mice do not show obvious defects, we show a striking synthetic effect in mice of the KO of Sac2 and the Sac domain mutation of SJ1 found in PD patients. These findings support a synergistic role of SJ1 and Sac2 on a PI4P pool whose dysfunction results in PD.