HtrA2 regulates α-Synuclein-mediated mitochondrial reactive oxygen species production in the mitochondria of microglia

Min Kyung Nam; Youngmo Seong; Gi Heon Jeong; Seung Ah Yoo; Hyangshuk Rhim

doi:10.1016/j.bbrc.2022.11.049

HtrA2 regulates α-Synuclein-mediated mitochondrial reactive oxygen species production in the mitochondria of microglia

Min Kyung Nam, Youngmo Seong, Gi Heon Jeong, Seung Ah Yoo, Hyangshuk Rhim

Department of Biomedicine & Health Science

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Aggregation and misfolding of α-Synuclein (α-Syn), a causative agent for Parkinson's disease (PD), and oxidative stress are tightly implicated in the pathogenesis of PD. Although more than 20 genes including HtrA2 have been identified as causative genes for PD, the molecular mechanisms underlying the pathophysiological functions between HtrA2 and α-Syn in the pathogenesis of PD remain unclear. This study shows that HtrA2 serine protease selectively recognizes and interacts with the NAC region of α-Syn. Interestingly, we found that HtrA2 causes proteolysis of α-Syn to prevent mitochondrial accumulation of α-Syn, thereby inhibiting the production of reactive oxygen species (ROS) in the mitochondria. We have further demonstrated that HtrA2 knockdown promotes α-Syn-mediated mitochondrial ROS production, thereby activating microglial cells. This study is the first to demonstrate that the HtrA2/α-Syn cellular partner may play a crucial role in the pathogenesis of PD and provide new insights into the pathological processes and effective therapeutic strategies for PD.

Original language	English
Pages (from-to)	84-93
Number of pages	10
Journal	Biochemical and Biophysical Research Communications
Volume	638
DOIs	https://doi.org/10.1016/j.bbrc.2022.11.049
State	Published - 1 Jan 2023

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea ( NRF ) grants funded by the Korea government (MIST) ( 2019R1A2B5B01070154 , 2019R1A5A2027588 , 2022R1A2C2092578 ) and the Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Health & Welfare) ( 21A0503L1 ).

Publisher Copyright:
© 2022 The Authors

Keywords

High-temperature requirement A2
Microglia
Parkinson's disease disease
Reactive oxygen species
α-Synuclein

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10.1016/j.bbrc.2022.11.049

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title = "HtrA2 regulates α-Synuclein-mediated mitochondrial reactive oxygen species production in the mitochondria of microglia",

abstract = "Aggregation and misfolding of α-Synuclein (α-Syn), a causative agent for Parkinson's disease (PD), and oxidative stress are tightly implicated in the pathogenesis of PD. Although more than 20 genes including HtrA2 have been identified as causative genes for PD, the molecular mechanisms underlying the pathophysiological functions between HtrA2 and α-Syn in the pathogenesis of PD remain unclear. This study shows that HtrA2 serine protease selectively recognizes and interacts with the NAC region of α-Syn. Interestingly, we found that HtrA2 causes proteolysis of α-Syn to prevent mitochondrial accumulation of α-Syn, thereby inhibiting the production of reactive oxygen species (ROS) in the mitochondria. We have further demonstrated that HtrA2 knockdown promotes α-Syn-mediated mitochondrial ROS production, thereby activating microglial cells. This study is the first to demonstrate that the HtrA2/α-Syn cellular partner may play a crucial role in the pathogenesis of PD and provide new insights into the pathological processes and effective therapeutic strategies for PD.",

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note = "Funding Information: This work was supported by the National Research Foundation of Korea ( NRF ) grants funded by the Korea government (MIST) ( 2019R1A2B5B01070154 , 2019R1A5A2027588 , 2022R1A2C2092578 ) and the Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Health & Welfare) ( 21A0503L1 ). Publisher Copyright: {\textcopyright} 2022 The Authors",

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AU - Nam, Min Kyung

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AU - Rhim, Hyangshuk

N1 - Funding Information: This work was supported by the National Research Foundation of Korea ( NRF ) grants funded by the Korea government (MIST) ( 2019R1A2B5B01070154 , 2019R1A5A2027588 , 2022R1A2C2092578 ) and the Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Health & Welfare) ( 21A0503L1 ). Publisher Copyright: © 2022 The Authors

PY - 2023/1/1

Y1 - 2023/1/1

N2 - Aggregation and misfolding of α-Synuclein (α-Syn), a causative agent for Parkinson's disease (PD), and oxidative stress are tightly implicated in the pathogenesis of PD. Although more than 20 genes including HtrA2 have been identified as causative genes for PD, the molecular mechanisms underlying the pathophysiological functions between HtrA2 and α-Syn in the pathogenesis of PD remain unclear. This study shows that HtrA2 serine protease selectively recognizes and interacts with the NAC region of α-Syn. Interestingly, we found that HtrA2 causes proteolysis of α-Syn to prevent mitochondrial accumulation of α-Syn, thereby inhibiting the production of reactive oxygen species (ROS) in the mitochondria. We have further demonstrated that HtrA2 knockdown promotes α-Syn-mediated mitochondrial ROS production, thereby activating microglial cells. This study is the first to demonstrate that the HtrA2/α-Syn cellular partner may play a crucial role in the pathogenesis of PD and provide new insights into the pathological processes and effective therapeutic strategies for PD.

AB - Aggregation and misfolding of α-Synuclein (α-Syn), a causative agent for Parkinson's disease (PD), and oxidative stress are tightly implicated in the pathogenesis of PD. Although more than 20 genes including HtrA2 have been identified as causative genes for PD, the molecular mechanisms underlying the pathophysiological functions between HtrA2 and α-Syn in the pathogenesis of PD remain unclear. This study shows that HtrA2 serine protease selectively recognizes and interacts with the NAC region of α-Syn. Interestingly, we found that HtrA2 causes proteolysis of α-Syn to prevent mitochondrial accumulation of α-Syn, thereby inhibiting the production of reactive oxygen species (ROS) in the mitochondria. We have further demonstrated that HtrA2 knockdown promotes α-Syn-mediated mitochondrial ROS production, thereby activating microglial cells. This study is the first to demonstrate that the HtrA2/α-Syn cellular partner may play a crucial role in the pathogenesis of PD and provide new insights into the pathological processes and effective therapeutic strategies for PD.

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HtrA2 regulates α-Synuclein-mediated mitochondrial reactive oxygen species production in the mitochondria of microglia

Abstract

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Catholic University of Korea Reports Findings in Nerve Tissue Proteins (HtrA2 regulates a-Synuclein-mediated mitochondrial reactive oxygen species production in the mitochondria of microglia)

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HtrA2 regulates α-Synuclein-mediated mitochondrial reactive oxygen species production in the mitochondria of microglia

Abstract

Bibliographical note

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Catholic University of Korea Reports Findings in Nerve Tissue Proteins (HtrA2 regulates a-Synuclein-mediated mitochondrial reactive oxygen species production in the mitochondria of microglia)

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