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Potential Pathophysiological Crosstalk between Parkin and FBXO7 Signalling Pathways

Mutations of F-box protein 7 [FBXO7] and Parkin, two proteins related to Ubiquitin-Proteasome System [UPS], are implicated in the pathogenesis of Dopamine [DA] neuron degeneration in Parkinson's Disease [PD], possibly involving impairment of UPS and mitophagy. Parkin is a HECT/RING hybrid ubiquitin E3 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. There are overlapping clinical features in Parkin and FBXO7 linked PD. One recent study demonstrates that FBXO7 can mediate mitochondrial translocation of Parkin under mitochondria impairment to initiate neuroprotective mitophagy. The signalling pathways of FBXO7 and Parkin may have complicated pathophysiological crosstalk, which should be implicated in PD pathogenesis and therapy. The FBXO7 may attract Parkin to impaired mitochondria to mediate ubiquitination of key substrates for mitophagy initiation. FBXO7 and Parkin may recognize each other as substrates reciprocally to promote their UPS degradation. Furthermore, FBXO7 may modulate Parkin E3 ligase activity. The aggregation-prone mutant FBXO7 has been shown to induce Parkin protein aggregation, which may lead to down regulation of available protective Parkin protein. Further studies are needed to decipher the complicated interactions between FBXO7 and Parkin.


Zhi Dong Zhou, Eng King Tan

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