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Precise control of mitophagy through ubiquitin proteasome system and deubiquitin proteases and their dysfunction in Parkinson’s disease

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초록

Parkinson’s disease (PD) is one of the most common neurodegenerativediseases in the elderly population and is caused bythe loss of dopaminergic neurons. PD has been predominantlyattributed to mitochondrial dysfunction. The structural alterationof α-synuclein triggers toxic oligomer formation in the neurons,which greatly contributes to PD. In this article, we discuss therole of several familial PD-related proteins, such as α-synuclein,DJ-1, LRRK2, PINK1, and parkin in mitophagy, which entails aselective degradation of mitochondria via autophagy. Defectivechanges in mitochondrial dynamics and their biochemical andfunctional interaction induce the formation of toxic α-synucleincontainingprotein aggregates in PD. In addition, these gene productsplay an essential role in ubiquitin proteasome system(UPS)-mediated proteolysis as well as mitophagy. Interestingly,a few deubiquitinating enzymes (DUBs) additionally modulatethese two pathways negatively or positively. Based on thesefindings, we summarize the close relationship between severalDUBs and the precise modulation of mitophagy. For example,the USP8, USP10, and USP15, among many DUBs are reportedto specifically regulate the K48- or K63-linked de-ubiquitinationreactions of several target proteins associated with the mitophagicprocess, in turn upregulating the mitophagy and protectingneuronal cells from α-synuclein-derived toxicity. In contrast,USP30 inhibits mitophagy by opposing parkin-mediated ubiquitinationof target proteins. Furthermore, the association betweenthese changes and PD pathogenesis will be discussed. Takentogether, although the functional roles of several PD-relatedgenes have yet to be fully understood, they are substantiallyassociated with mitochondrial quality control as well as UPS. Therefore, a better understanding of their relationship providesvaluable therapeutic clues for appropriate management strategies.

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerativediseases in the elderly population and is caused bythe loss of dopaminergic neurons. PD has been predominantlyattributed to mitochondrial dysfunction. The structural alterationof α-synuclein triggers toxic oligomer formation in the neurons,which greatly contributes to PD. In this article, we discuss therole of several familial PD-related proteins, such as α-synuclein,DJ-1, LRRK2, PINK1, and parkin in mitophagy, which entails aselective degradation of mitochondria via autophagy. Defectivechanges in mitochondrial dynamics and their biochemical andfunctional interaction induce the formation of toxic α-synucleincontainingprotein aggregates in PD. In addition, these gene productsplay an essential role in ubiquitin proteasome system(UPS)-mediated proteolysis as well as mitophagy. Interestingly,a few deubiquitinating enzymes (DUBs) additionally modulatethese two pathways negatively or positively. Based on thesefindings, we summarize the close relationship between severalDUBs and the precise modulation of mitophagy. For example,the USP8, USP10, and USP15, among many DUBs are reportedto specifically regulate the K48- or K63-linked de-ubiquitinationreactions of several target proteins associated with the mitophagicprocess, in turn upregulating the mitophagy and protectingneuronal cells from α-synuclein-derived toxicity. In contrast,USP30 inhibits mitophagy by opposing parkin-mediated ubiquitinationof target proteins. Furthermore, the association betweenthese changes and PD pathogenesis will be discussed. Takentogether, although the functional roles of several PD-relatedgenes have yet to be fully understood, they are substantiallyassociated with mitochondrial quality control as well as UPS. Therefore, a better understanding of their relationship providesvaluable therapeutic clues for appropriate management strategies.

참고문헌 (71)

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