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

Zhi Dong Zhou1, Shao Ping Xie2, Sushmitha Sathiyamoorthy2

  • 1National 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.

Human Molecular Genetics
|August 28, 2015
PubMed

Insights

Mutant F-box protein 7 (FBXO7) inhibits mitophagy, causing cell damage linked to Parkinson's disease. Therapies targeting FBXO7 aggregation show potential for treating neurodegenerative disorders.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Mutations in the F-box protein 7 (FBXO7) gene are linked to autosomal recessive juvenile-onset Parkinson's disease (PARK 15).
  • Wild-type (WT) FBXO7 functions as a stress response protein with dual cytoprotective and neurotoxic roles.

Purpose of the Study:

  • To investigate the role of WT and mutant FBXO7 in cellular stress response and mitophagy.
  • To explore the impact of FBXO7 aggregation on neurodegeneration in Parkinson's disease (PD) and Alzheimer's disease (AD).

Main Methods:

  • Examined FBXO7 localization and aggregation in mitochondria under stress conditions.
  • Assessed the effects of various compounds (Proline, GSH, CoQ10, PHB1) on FBXO7 aggregation.
  • Utilized transgenic Drosophila models and human fibroblast cells from PD patients to study FBXO7's in vivo effects.

Main Results:

  • WT FBXO7 facilitates mitophagy for cell protection, while mutant FBXO7 inhibits it.
  • FBXO7 mutations exacerbate deleterious mitochondrial aggregation under stress.
  • Overexpression of WT FBXO7 can induce protein aggregation and dopamine neuron degeneration.
  • Elevated FBXO7 expression and aggregation are observed in PD patient cells and in the brains of PD and AD patients.

Conclusions:

  • FBXO7 plays a critical role in mitophagy and cellular response to stress.
  • FBXO7 aggregation is a key pathological feature in FBXO7-linked neurodegeneration.
  • FBXO7 represents a potential therapeutic target for PD and other neurodegenerative diseases involving FBXO7 dysfunction.

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