title: F-box protein 7 mutations promote protein aggregation in mitochondria and inhibit mitophagy.
abstract: The mutations of F-box protein 7 (FBXO7) gene (T22M, R378G and R498X) are associated with a severe form of autosomal recessive juvenile-onset Parkinson's disease (PD) (PARK 15). Here we demonstrated that wild-type (WT) FBXO7 is a stress response protein and it can play both cytoprotective and neurotoxic roles. The WT FBXO7 protein is vital to cell mitophagy and can facilitate mitophagy to protect cells, whereas mutant FBXO7 inhibits mitophagy. Upon stress, the endogenous WT FBXO7 gets up-regulated, concentrates into mitochondria and forms FBXO7 aggregates in mitochondria. However, FBXO7 mutations aggravate deleterious FBXO7 aggregation in mitochondria. The FBXO7 aggregation and toxicity can be alleviated by Proline, glutathione (GSH) and coenzyme Q10, whereas deleterious FBXO7 aggregation in mitochondria can be aggravated by prohibitin 1 (PHB1), a mitochondrial protease inhibitor. The overexpression of WT FBXO7 could lead to FBXO7 protein aggregation and dopamine neuron degeneration in transgenic Drosophila heads. The elevated FBXO7 expression and aggregation were identified in human fibroblast cells from PD patients. FBXO7 can also form aggregates in brains of PD and Alzheimer's disease. Our study provides novel pathophysiologic insights and suggests that FBXO7 may be a potential therapeutic target in FBXO7-linked neuron degeneration in PD.
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore, Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, Singapore.
authors: Zhi Dong
authors: ZD
authors: Zhou
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
authors: Shao Ping
authors: SP
authors: Xie
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
authors: Sushmitha
authors: S
authors: Sathiyamoorthy
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
authors: Wuan Ting
authors: WT
authors: Saw
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
authors: Tan Ye
authors: TY
authors: Sing
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
authors: Shin Hui
authors: SH
authors: Ng
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
authors: Heidi Pek Hup
authors: HP
authors: Chua
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
authors: Alyssa Mei Yan
authors: AM
authors: Tang
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
authors: Fathima
authors: F
authors: Shaffra
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
authors: Zeng
authors: Z
authors: Li
authors: Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, Singapore.
authors: Hongyan
authors: H
authors: Wang
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
authors: Patrick Ghim Hoe
authors: PG
authors: Ho
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors: Mitchell Kim Peng
authors: MK
authors: Lai
authors: Department of Neurology, Singapore General Hospital, Outram Road, Singapore, Singapore and.
authors: Dario C
authors: DC
authors: Angeles
authors: Department of Biological Science, National University of Singapore, 14 Science Drive 4, Singapore, Singapore.
authors: Tit Meng
authors: TM
authors: Lim
authors: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore, Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, Singapore, Department of Neurology, Singapore General Hospital, Outram Road, Singapore, Singapore and gnrtek@sgh.com.sg.
authors: Eng-King
authors: EK
authors: Tan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004330:Drosophila; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy / Q000235:genetics; D009154:Mutation; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D000091402:Prohibitins; D066329:Protein Aggregates / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; C489149:FBXO7 protein, human; C000717328:PHB protein, human; D000091402:Prohibitins; D066329:Protein Aggregates; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein