Abstract
Parkinson’s disease (PD) is characterized by the progressive loss of midbrain dopamine neurons in the substantia nigra. Mutations in the F-box only protein 7 gene (Fbxo7) have been reported to cause an autosomal recessive form of early-onset familial PD. FBXO7 is a part of the SKP1-Cullin1-F-box (SCF) E3 ubiquitin ligase complex, which mediates ubiquitination of numerous substrates. FBXO7 also regulates mitophagy, cell growth, and proteasome activity. A member of the FOXO family, the transcription factor FOXO4, is also known to modulate several cellular responses, including cell cycle progression and apoptosis; however, the relationship between FBXO7 and FOXO4 has not been investigated. In this study, we determined that FBXO7 binds to FOXO4 and negatively regulates intracellular FOXO4 levels. Interestingly, we also found that FBXO7-mediated degradation of FOXO4 did not occur through either of two major proteolysis systems, the ubiquitin-proteasome system or the lysosome-autophagy pathway, although it was blocked by a caspase 8-specific inhibitor and caspase 8-knockdown. Moreover, intracellular FOXO4 levels were greatly reduced in dopaminergic MN9D cells following treatment with neurotoxic 6-hydroxydopamine (6-OHDA), which was produced upon FBXO7-mediated and caspase 8-mediated proteolysis. Taken together, these results suggest that FOXO4 is negatively regulated in FBXO7-linked PD through caspase 8 activation, suppressing the cytoprotective effect of FOXO4 during 6-OHDA-induced neuronal cell death.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects 1% of the population over the age of 60 years [1]
Our findings suggest that the functional relationship between F-box only protein 7 (FBXO7) and FOXO4 may play a role in 6-OHDA-induced neuronal cell death, as well as PD pathogenesis
Immunohistochemical analysis of human neuroblastoma SH-SY5Y cells revealed that endogenous FBXO7 and FOXO4 colocalized in cells (Fig. 1E)
Summary
Received for publication, June 15, 2021, and in revised form, November 5, 2021 Published, Papers in Press, November 17, 2021, https://doi.org/10.1016/j.jbc.2021.101426 Su Hyoun Lee, Sungyeon Jung, Yun Ju Lee, Minju Hyun, and Kwang Chul Chung* From the Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
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