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Review
doi: 10.1186/s13041-016-0218-2.

Linking F-box protein 7 and parkin to neuronal degeneration in Parkinson's disease (PD)

Affiliations
Review

Linking F-box protein 7 and parkin to neuronal degeneration in Parkinson's disease (PD)

Zhi Dong Zhou et al. Mol Brain..

Abstract

Mutations of F-box protein 7 (FBXO7) and Parkin, two proteins in ubiquitin-proteasome system (UPS), are both implicated in pathogenesis of dopamine (DA) neuron degeneration in Parkinson's disease (PD). Parkin is a HECT/RING hybrid ligase that physically receives ubiquitin on its catalytic centre and passes ubiquitin onto its substrates, whereas FBXO7 is an adaptor protein in Skp-Cullin-F-box (SCF) SCF(FBXO7) ubiquitin E3 ligase complex to recognize substrates and mediate substrates ubiquitination by SCF(FBXO7) E3 ligase. Here, we discuss the overlapping pathophysiologic mechanisms and clinical features linking Parkin and FBXO7 with autosomal recessive PD. Both proteins play an important role in neuroprotective mitophagy to clear away impaired mitochondria. Parkin can be recruited to impaired mitochondria whereas cellular stress can promote FBXO7 mitochondrial translocation. PD-linked FBXO7 can recruit Parkin into damaged mitochondria and facilitate its aggregation. WT FBXO7, but not PD-linked FBXO7 mutants can rescue DA neuron degeneration in Parkin null Drosophila. A better understanding of the common pathophysiologic mechanisms of these two proteins could unravel specific pathways for targeted therapy in PD.

Keywords: FBXO7; Mitochondria; Mitophagy; Parkin; Parkinson’s disease; Protein aggregation; Proteotoxicity; Ubiquitin proteasome system.

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Figures

Fig. 1
Fig. 1
Molecular structure and PD-linked generic variations of FBXO7 and Parkin. The molecular structures of FBXO7 (a) and Parkin (b) together with indications of PD-linked mutations are respectively illustrated. The detailed sites of PD-linked generic variations of frameshift or missense mutations of FBXO7 and Parkin are pointed with red or green colour arrows respectively
Fig. 2
Fig. 2
Physiological roles of FBXO7 and Parkin in UPS.a, the physiological roles of FBXO7 in SCFFBXO7 E3 ligase complex. FBXO7 acts as an adaptor protein to recognize and interact with its substrates for SCFFBXO7 E3 ligase mediated ubiquitination. After interaction with its substrates, FBXO7 will bind with SKP1 which further interact with Cul1 and ROC1 to form functional SCFFBXO7 E3 ligase complex. The SCFFBXO7 E3 ligase will mediate E2 ligase induced ubiquitination of FBXO7 substrates.b, the physiological roles of Parkin. After interaction with its substrates, Parkin exerts its E3 ligase activity to mediate ubiquitination of its substrates by E2 ligase.c, detailed procedures of SCFFBXO7 and Parkin E3 ligases mediated ubiquitination and proteasome degradation of substrates. (Left), SCFFBXO7 E3 ligase mediated substrates recognition, ubiquitination and proteasomal degradation. (Right), Parkin mediated substrates recognition, ubiquitination and proteasomal degradation
Fig. 3
Fig. 3
Potential pathogenesis of FBXO7 and Parkin mutations induced neuron degeneration in PD. FBXO7 mutations can lead to deleterious FBXO7 protein aggregation, inhibition of mitophagy process and impairment of FBXO7-linked UPS functions. Mutant FBXO7 proteins can form stress dependent toxic protein aggregates in mitochondria. The impaired mitophagy will also impair mitochondria functions. Besides, the impairment of FBXO7-linked UPS function may lead to accumulation of some toxic FBXO7 targets. All these alterations may converge and contribute to FBXO7 mutations induced neuron degeneration in PARK15. However Parkin mutations induced mitophagy impairment and accumulation of toxic Parkin targets may contribute to neuron degeneration in PARK2
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