Parkin regulates neuronal lipid homeostasis through SREBP2-lipoprotein lipase pathway—implications for Parkinson’s disease
| Autor: | Willcyn Tang, John Thundyil, Grace Gui Yin Lim, Teddy J W Tng, Sean Qing Zhang Yeow, Aditya Nair, Chou Chai, Tso-Pang Yao, Kah-Leong Lim |
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| Přispěvatelé: | Lee Kong Chian School of Medicine (LKCMedicine) |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Human Molecular Genetics. 32:1466-1482 |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Abnormal lipid homeostasis has been observed in the brain of Parkinson's disease (PD) patients and experimental models, although the mechanism underlying this phenomenon is unclear. Notably, previous studies have reported that the PD-linked protein Parkin functionally interacts with important lipid regulators, including Sterol Regulatory Element-Binding Proteins (SREBPs) and cluster of differentiation 36 (CD36). Here, we demonstrate a functional relationship between Parkin and lipoprotein lipase (LPL), a triglyceride lipase that is widely expressed in the brain. Using a human neuroblastoma cell line and a Parkin knockout mouse model, we demonstrate that Parkin expression level positively correlates with neuronal LPL protein level and activity. Importantly, our study identified SREBP2, a major regulator of sterol and fatty acid synthesis, as a potential mediator between Parkin and LPL. Supporting this, SREBP2 genetic ablation abolished Parkin effect on LPL expression. We further demonstrate that Parkin-LPL pathway regulates the formation of intracellular lipid droplets, and that this pathway is upregulated upon exposure to PD-linked oxidative stress induced by rotenone. Finally, we show that inhibition of either LPL or SREBP2 exacerbates rotenone-induced cell death. Taken together, our findings reveal a novel pathway linking Parkin, SREBP2 and LPL in neuronal lipid homeostasis that may be relevant to the pathogenesis of PD. Ministry of Education (MOE) Ministry of Health (MOH) National Medical Research Council (NMRC) Published version Singapore Ministry of Health Open Fund-Large Collaborative Grant (MOH-OFLCG18May-0002), Lee Kong Chian School of Medicine Start Up Grant from Singapore Ministry of Education (#002642-00001), and National Medical Research CouncilTranslational and Clinical Research (NMRC/TCR/013-NNI/2014) awarded to K.L.L. and Khoo Pilot Award (Duke/Duke-NUS/RECA (Pilot)/2016/0023) awarded to K.L.L. and T.P.Y. |
| Databáze: | OpenAIRE |
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