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) SCFFBXO7 ubiquitin E3 ligase complex to recognize substrates and mediate substrates ubiquitination by SCFFBXO7 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.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative disorder characterized by chronic and progressive loss of dopaminergic neurons in substansia nigra pars compacta (SN)
Overexpression of wild type (WT) F-box protein 7 (FBXO7), but not PD-linked FBXO7 mutants, can rescue degeneration of DA neurons in Parkin null Drosophila [51]. These findings suggest that FBXO7 may function in a common pathway with Parkin/PINK1 protein pair to modulate mitophagy, whereas FBXO7 mutations lead to loss of these functions
Clinical aspects of Parkin and FBXO7 linked PD carriers Homozygous or heterozygous mutations in Parkin and FBXO7 are both associated with early onset autosomal recessive Parkinsonism (PARK2 and PARK15)
Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative disorder characterized by chronic and progressive loss of dopaminergic neurons in substansia nigra pars compacta (SN). It was reported that proteasome inhibition induced UPS impairment can result in accumulation of misfolded proteins and deleterious protein aggregates, contributing to neuronal dysfunction and demise [21]. Impairment of UPS in PD pathogenesis was established with mutations of Parkin, a HECT/RING hybrid ubiquitin E3 ligase [27, 28], and other genetic forms of PD [20, 29].
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