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- Title
PINK1 and Parkin regulate IP<sub>3</sub>R-mediated ER calcium release.
- Authors
Ham, Su Jin; Yoo, Heesuk; Woo, Daihn; Lee, Da Hyun; Park, Kyu-Sang; Chung, Jongkyeong
- Abstract
Although defects in intracellular calcium homeostasis are known to play a role in the pathogenesis of Parkinson's disease (PD), the underlying molecular mechanisms remain unclear. Here, we show that loss of PTEN-induced kinase 1 (PINK1) and Parkin leads to dysregulation of inositol 1,4,5-trisphosphate receptor (IP3R) activity, robustly increasing ER calcium release. In addition, we identify that CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) functions downstream of Parkin to directly control IP3R. Both genetic and pharmacologic suppression of CISD1 and its Drosophila homolog CISD (also known as Dosmit) restore the increased ER calcium release in PINK1 and Parkin null mammalian cells and flies, respectively, demonstrating the evolutionarily conserved regulatory mechanism of intracellular calcium homeostasis by the PINK1-Parkin pathway. More importantly, suppression of CISD in PINK1 and Parkin null flies rescues PD-related phenotypes including defective locomotor activity and dopaminergic neuronal degeneration. Based on these data, we propose that the regulation of ER calcium release by PINK1 and Parkin through CISD1 and IP3R is a feasible target for treating PD pathogenesis. Loss of two PD genes, PINK1 and Parkin, leads to a robust increase in ER calcium release. Here, the authors show that suppression of IP3R activity via inhibiting CISD1 is sufficient to rescue the PD-related phenotypes in PINK1 or Parkin null animal models.
- Subjects
PARKIN (Protein); CALCIUM; SUPPRESSOR mutation; PARKINSON'S disease; INTRACELLULAR calcium; IRON
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40929-z