2. Academic Validation
  3. F-box protein 7 mutations promote protein aggregation in mitochondria and inhibit mitophagy

F-box protein 7 mutations promote protein aggregation in mitochondria and inhibit mitophagy

  • Hum Mol Genet. 2015 Nov 15;24(22):6314-30. doi: 10.1093/hmg/ddv340.
Zhi Dong Zhou 1,  Shao Ping Xie 2,  Sushmitha Sathiyamoorthy 2,  Wuan Ting Saw 2,  Tan Ye Sing 2,  Shin Hui Ng 2,  Heidi Pek Hup Chua 2,  Alyssa Mei Yan Tang 2,  Fathima Shaffra 2,  Zeng Li 2,  Hongyan Wang 3,  Patrick Ghim Hoe Ho 2,  Mitchell Kim Peng Lai 4,  Dario C Angeles 5,  Tit Meng Lim 6,  Eng-King Tan 7
Affiliations

Affiliations

  • 1 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.
  • 2 National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
  • 3 Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, Singapore.
  • 4 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 5 Department of Neurology, Singapore General Hospital, Outram Road, Singapore, Singapore and.
  • 6 Department of Biological Science, National University of Singapore, 14 Science Drive 4, Singapore, Singapore.
  • 7 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.
PMID: 26310625 DOI: 10.1093/hmg/ddv340
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.

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