The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP3, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson's disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models. In primary neurons, knockdown or pharmacological inhibition of ITPKB increased levels of phosphorylated, insoluble alpha-synuclein pathology following treatment with alpha-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced alpha-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown increases intracellular calcium levels in neurons, leading to an accumulation of calcium in mitochondria that increases respiration and inhibits the initiation of autophagy, suggesting that ITPKB regulates alpha-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondria! calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondria! calcium uniporter complex, which was also sufficient to reduce alpha-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of alpha-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD.

Automated summary

ITPKB is negatively regulating alpha-synuclein aggregation by inhibiting ER-to-mitochondria calcium transport, suggesting modulation of this pathway as a potential therapeutic strategy for sporadic PD.