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

Zhou ZD, Sathiyamoorthy S, Angeles DC, Tan EK - Mol Brain (2016)

Bottom Line: 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.A better understanding of the common pathophysiologic mechanisms of these two proteins could unravel specific pathways for targeted therapy in PD.

View Article: PubMed Central - PubMed

Affiliation: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore. zhidong_zhou@nni.com.sg.

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 Drosophila. A better understanding of the common pathophysiologic mechanisms of these two proteins could unravel specific pathways for targeted therapy in PD.

No MeSH data available.


Related in: MedlinePlus

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
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Fig2: 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

Mentions: There are overlapping and divergent pathophysiological roles between Parkin and FBXO7. The physiological roles of Parkin and FBXO7 are summarized in Fig. 2. Both Parkin and FBXO7 play a common role in UPS [35, 67, 98]. The Parkin is a HECT/RING hybrid ligase, whereas FBXO7 is an adaptor protein in Skp-Cullin-F-box (SCF) SCFFBXO7 ubiquitin E3 ligase complex [12, 43]. Parkin and FBXO7 are both implicated in tumorigenesis [51]. WT Parkin and FBXO7 can both be cytoprotective, whereas their PD-linked mutants are all deleterious to DA neurons. Both WT Parkin and FBXO7 promote mitophagy, whereas their PD-linked mutants impair mitophagy. Furthermore FBXO7 and Parkin have reciprocal interactions, suggesting overlaps of their signalling pathways. WT FBXO7 but not PD-linked FBXO7 mutants can rescue lack of Parkin induced PD symptoms in flies [51]. FBXO7 was reported to mediate mitochondria translocation of Parkin [51]. Therefore FBXO7 may act upstream of Parkin and have Parkin independent complicated functions. Our recently findings show that FBXO7 proteins can form deleterious aggregates in mitochondria [26]. However no reports have shown that Parkin can form protein aggregates in mitochondria. The similarities and differences of their pathophysiological roles are summarized in Table 2.Fig. 2


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

Zhou ZD, Sathiyamoorthy S, Angeles DC, Tan EK - Mol Brain (2016)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4835861&req=5

Fig2: 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
Mentions: There are overlapping and divergent pathophysiological roles between Parkin and FBXO7. The physiological roles of Parkin and FBXO7 are summarized in Fig. 2. Both Parkin and FBXO7 play a common role in UPS [35, 67, 98]. The Parkin is a HECT/RING hybrid ligase, whereas FBXO7 is an adaptor protein in Skp-Cullin-F-box (SCF) SCFFBXO7 ubiquitin E3 ligase complex [12, 43]. Parkin and FBXO7 are both implicated in tumorigenesis [51]. WT Parkin and FBXO7 can both be cytoprotective, whereas their PD-linked mutants are all deleterious to DA neurons. Both WT Parkin and FBXO7 promote mitophagy, whereas their PD-linked mutants impair mitophagy. Furthermore FBXO7 and Parkin have reciprocal interactions, suggesting overlaps of their signalling pathways. WT FBXO7 but not PD-linked FBXO7 mutants can rescue lack of Parkin induced PD symptoms in flies [51]. FBXO7 was reported to mediate mitochondria translocation of Parkin [51]. Therefore FBXO7 may act upstream of Parkin and have Parkin independent complicated functions. Our recently findings show that FBXO7 proteins can form deleterious aggregates in mitochondria [26]. However no reports have shown that Parkin can form protein aggregates in mitochondria. The similarities and differences of their pathophysiological roles are summarized in Table 2.Fig. 2

Bottom Line: 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.A better understanding of the common pathophysiologic mechanisms of these two proteins could unravel specific pathways for targeted therapy in PD.

View Article: PubMed Central - PubMed

Affiliation: National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore. zhidong_zhou@nni.com.sg.

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 Drosophila. A better understanding of the common pathophysiologic mechanisms of these two proteins could unravel specific pathways for targeted therapy in PD.

No MeSH data available.


Related in: MedlinePlus