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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

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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Fig3: 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

Mentions: It is suggested by recent findings that WT FBXO7 protein can have dual protective as well as toxic functions [26]. Stress of cells can up-regulate FBXO7 expression to protect cells. However increased FBXO7 expression under stress can lead to formation of deleterious FBXO7 protein aggregates, especially in mitochondria [26]. PD-linked FBXO7 mutations aggravate toxic FBXO7 aggregation in mitochondria [26]. FBXO7 aggregation in mitochondria can impair mitochondria integrity, promote generation of reactive oxygen species (ROS) and finally lead to cell demise [26]. However FBXO7 aggregation induced proteotoxicity to cells can be alleviated by protein aggregation inhibitors such as L-proline, but be aggravated by prohibitin, a nature mitochondrial protease inhibitor [26]. It is proposed that FBXO7 aggregation, mitochondria impairment and ROS production may form a positive feedback loop implicated in FBXO7-linked neuron degeneration [26]. Such a situation can be aggravated by FBXO7 mutations induced mitophagy inhibition, contributing to PARK15 (Fig. 3) [26].


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)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: 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
Mentions: It is suggested by recent findings that WT FBXO7 protein can have dual protective as well as toxic functions [26]. Stress of cells can up-regulate FBXO7 expression to protect cells. However increased FBXO7 expression under stress can lead to formation of deleterious FBXO7 protein aggregates, especially in mitochondria [26]. PD-linked FBXO7 mutations aggravate toxic FBXO7 aggregation in mitochondria [26]. FBXO7 aggregation in mitochondria can impair mitochondria integrity, promote generation of reactive oxygen species (ROS) and finally lead to cell demise [26]. However FBXO7 aggregation induced proteotoxicity to cells can be alleviated by protein aggregation inhibitors such as L-proline, but be aggravated by prohibitin, a nature mitochondrial protease inhibitor [26]. It is proposed that FBXO7 aggregation, mitochondria impairment and ROS production may form a positive feedback loop implicated in FBXO7-linked neuron degeneration [26]. Such a situation can be aggravated by FBXO7 mutations induced mitophagy inhibition, contributing to PARK15 (Fig. 3) [26].

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