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Absence of Sac2/INPP5F enhances the phenotype of a Parkinson’s disease mutation of synaptojanin 1.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 6/2/2020, Vol. 117 Issue 22, p1-7, 7p
- Publication Year :
- 2020
-
Abstract
- 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 synapto-janin 1 (SJ1/PARK20), a phosphoinositide phosphatase implicatedin synaptic vesicle recycling, results in PD. The gene encoding Sac2/INPP5F, another Sac domain-containing protein, is located within aPD risk locus identified by genome-wide association studies. Knock-In mice carrying the SJ1 patient mutation (SJ1<superscript>RQ</superscript>KI) 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 SJ1<superscript>RQ</superscript>KImice. The abnormal accumulation of endocytic factors observed at synapses of cultured SJ1<superscript>RQ</superscript>KI neurons was more severe in double-mutant neurons. Our results suggest that SJ1 and Sac2have partially overlapping functions and are consistent with a potential role of Sac2 as a PD risk gene. [ABSTRACT FROM AUTHOR]
- Subjects :
- PARKINSON'S disease
SYNAPTIC vesicles
NERVE endings
STUNTED growth
KNOCKOUT mice
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 117
- Issue :
- 22
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 143582435
- Full Text :
- https://doi.org/10.1073/pnas.2004335117