Investigation of USP30 inhibition to enhance Parkin-mediated mitophagy: tools and approaches.
Investigation of USP30 inhibition to enhance Parkin-mediated mitophagy: tools and approaches.
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DOI：
10.1042/bcj20210508
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发表时间：
2021-12-10
期刊：
影响因子：
--
通讯作者：
Ketteler R
中科院分区：
文献类型：
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作者：
Tsefou E;Walker AS;Clark EH;Hicks AR;Luft C;Takeda K;Watanabe T;Ramazio B;Staddon JM;Briston T;Ketteler R
Mitochondrial dysfunction is implicated in Parkinson disease (PD). Mutations in Parkin, an E3 ubiquitin ligase, can cause juvenile-onset Parkinsonism, probably through impairment of mitophagy. Inhibition of the de-ubiquitinating enzyme USP30 may counter this effect to enhance mitophagy. Using different tools and cellular approaches, we wanted to independently confirm this claimed role for USP30. Pharmacological characterisation of additional tool compounds that selectively inhibit USP30 are reported. The consequence of USP30 inhibition by these compounds, siRNA knockdown and overexpression of dominant-negative USP30 on the mitophagy pathway in different disease-relevant cellular models was explored. Knockdown and inhibition of USP30 showed increased p-Ser65-ubiquitin levels and mitophagy in neuronal cell models. Furthermore, patient-derived fibroblasts carrying pathogenic mutations in Parkin showed reduced p-Ser65-ubiquitin levels compared with wild-type cells, levels that could be restored using either USP30 inhibitor or dominant-negative USP30 expression. Our data provide additional support for USP30 inhibition as a regulator of the mitophagy pathway.
