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: Zhi Dong Zhou, Shao Ping Xie, Sushmitha Sathiyamoorthy, Wuan Ting Saw, Tan Ye Sing, Shin Hui Ng, Heidi Pek Hup Chua, Alyssa Mei Yan Tang, Fathima Shaffra, Zeng Li, Hongyan Wang, Patrick Ghim Hoe Ho, Mitchell Kim Peng Lai, Dario C Angeles, Tit Meng Lim, Eng-King Tan
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 22 Pg. 6314-30 (Nov 15 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 26310625 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• F-Box Proteins
• FBXO7 protein, human
• PHB protein, human
• Prohibitins
• Protein Aggregates
• Ubiquitin-Protein Ligases
• parkin protein

Topics

• Animals
• Cells, Cultured
• Drosophila
• F-Box Proteins (genetics, metabolism)
• Female
• Humans
• Mice
• Mice, Transgenic
• Mitochondria (metabolism)
• Mitophagy (genetics)
• Mutation
• Parkinsonian Disorders (genetics, metabolism)
• Pregnancy
• Prohibitins
• Protein Aggregates (genetics)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Ubiquitination