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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

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
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Fig1: 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

Mentions: The FBXO7 R378G mutation was first reported to be linked to early-onset Parkinsonian (PARK15) in 2008 [33]. In 2009 R498X and T22M FBXO7 mutations were subsequently indentified to induce autosomal recessive, early-onset Parkinsonian-pyramidal syndrome [17, 33]. The PARK15 patients presented with Babinski signs and spastic weakness [18, 34, 35]. Parkinsonism with resting tremor, bradykinesia and postural instability developed in later stages of some PARK15 patients [36]. Recently a new FBXO7 L34R mutation causing typical L-dopa-responsive Parkinsonism was reported in a Turkish family [37]. The L34R mutation is similar to T22M mutation, which is predicted to affect the UBL domain of FBXO7 isoform 1 protein and is associated with disturbed nuclear localization of FBXO7 protein [37]. Another heterozygous mutation (R481C) of FBXO7 was reported in an Italian family [38, 39]. As these patients also carried other genetic variants related to PD, the pathogenicity of R481C FBXO7 mutant still remains to be clarified [17, 18]. However a potential protective Y52C FBXO7 polymorphism is recently identified [40]. The molecular structure of FBXO7 protein and PARK15 linked FBXO7 mutations or variations are summarized in Fig. 1a.Fig. 1


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)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835861&req=5

Fig1: 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
Mentions: The FBXO7 R378G mutation was first reported to be linked to early-onset Parkinsonian (PARK15) in 2008 [33]. In 2009 R498X and T22M FBXO7 mutations were subsequently indentified to induce autosomal recessive, early-onset Parkinsonian-pyramidal syndrome [17, 33]. The PARK15 patients presented with Babinski signs and spastic weakness [18, 34, 35]. Parkinsonism with resting tremor, bradykinesia and postural instability developed in later stages of some PARK15 patients [36]. Recently a new FBXO7 L34R mutation causing typical L-dopa-responsive Parkinsonism was reported in a Turkish family [37]. The L34R mutation is similar to T22M mutation, which is predicted to affect the UBL domain of FBXO7 isoform 1 protein and is associated with disturbed nuclear localization of FBXO7 protein [37]. Another heterozygous mutation (R481C) of FBXO7 was reported in an Italian family [38, 39]. As these patients also carried other genetic variants related to PD, the pathogenicity of R481C FBXO7 mutant still remains to be clarified [17, 18]. However a potential protective Y52C FBXO7 polymorphism is recently identified [40]. The molecular structure of FBXO7 protein and PARK15 linked FBXO7 mutations or variations are summarized in Fig. 1a.Fig. 1

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