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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 1; pp. 1 - 11
• Main Authors: Apicco, Daniel J., Shlevkov, Evgeny, Nezich, Catherine L., Tran, David T., Guilmette, Edward, Nicholatos, Justin W., Bantle, Collin M., Chen, Yi, Glajch, Kelly E., Abraham, Neeta A., Dang, Lan T., Kaynor, G. Campbell, Tsai, Ellen A., Nguyen, Khanh-Dung H., Groot, Joost, Liu, YuTing, Weihofen, Andreas, Hurt, Jessica A., Runz, Heiko, Hirst, Warren D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05-01-2021
• Subjects: Agglomeration; alpha-Synuclein - metabolism; Animal models; Animals; Autophagy; Autophagy - genetics; Biological Sciences; Calcium; Calcium (intracellular); Calcium (mitochondrial); Calcium (reticular); Calcium - metabolism; Calcium transport; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Fibrils; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Inositol 1,4,5-trisphosphate receptors; Kinases; Lipid kinase; Lipids; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Movement disorders; Neurodegenerative diseases; Neurons; Neurons - metabolism; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Pathology; Phagocytosis; Pharmacology; Phenotypes; Phosphorylation - genetics; Phosphotransferases (Alcohol Group Acceptor) - genetics; Pretreatment; Respiration; Risk management; Signal Transduction - genetics; Synuclein; Synucleinopathies - genetics; Synucleinopathies - metabolism; genetics; mitochondria; Parkinson’s disease; α-synuclein; calcium signaling
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2006476118

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 α-synuclein pathology following treatment with α-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced α-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 α-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondrial calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondrial calcium uniporter complex, which was also sufficient to reduce α-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of α-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD.