Absence of Sac2/INPP5F enhances the phenotype of a Parkinson’s disease mutation of synaptojanin 1
| العنوان: | Absence of Sac2/INPP5F enhances the phenotype of a Parkinson’s disease mutation of synaptojanin 1 |
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| المؤلفون: | Yumei Wu, Mian Cao, Daehun Park, Pietro De Camilli |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | medicine.medical_specialty, Parkinson's disease, Dopamine, INPP5F, Phosphatase, Endocytic cycle, Biology, Mice, Internal medicine, medicine, endocytosis, Animals, Humans, Synaptic vesicle recycling, synaptojanin 1, Gene, Sac2, Mice, Knockout, Nerve Endings, Multidisciplinary, Inositol Polyphosphate 5-Phosphatases, Dopaminergic, PI4P, Parkinson Disease, Biological Sciences, medicine.disease, Molecular biology, Phenotype, Mice, Inbred C57BL, Endocrinology, Mutation, Synapses, Knockout mouse, Neuroscience, Genome-Wide Association Study |
| الوصف: | 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. Numerous genes whose mutations cause, or increase the risk of, Parkinson’s disease (PD) have been identified. An inactivating mutation (R258Q) in the Sac inositol phosphatase domain of synaptojanin 1 (SJ1/PARK20), a phosphoinositide phosphatase implicated in synaptic vesicle recycling, results in PD. The gene encoding Sac2/INPP5F, another Sac domain-containing protein, is located within a PD risk locus identified by genome-wide association studies. Knock-In mice carrying the SJ1 patient mutation (SJ1RQKI) exhibit PD features, while Sac2 knockout mice (Sac2KO) do not have obvious neurologic defects. We report a “synthetic” effect of the SJ1 mutation and the KO of Sac2 in mice. Most mice with both mutations died perinatally. The occasional survivors had stunted growth, died within 3 wk, and showed abnormalities of striatal dopaminergic nerve terminals at an earlier stage than SJ1RQKI mice. The abnormal accumulation of endocytic factors observed at synapses of cultured SJ1RQKI neurons was more severe in double-mutant neurons. Our results suggest that SJ1 and Sac2 have partially overlapping functions and are consistent with a potential role of Sac2 as a PD risk gene. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d2d0755d00b65cdc259436cd535ae3c9 https://doi.org/10.1073/pnas.2004335117 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....d2d0755d00b65cdc259436cd535ae3c9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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