PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease

Hyejin Park; Tae In Kam; Hanjing Peng; Shih Ching Chou; Amir A. Mehrabani-Tabari; Jae Jin Song; Xiling Yin; Senthilkumar S. Karuppagounder; George K. Umanah; A. V.Subba Rao; Yu Ree Choi; Akanksha Aggarwal; Sohyun Chang; Hyunhee Kim; Jiyoung Byun; Jun O. Liu; Ted M. Dawson; Valina L. Dawson

doi:10.1016/j.cell.2022.04.020

PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease

Hyejin Park, Tae In Kam, Hanjing Peng, Shih Ching Chou, Amir A. Mehrabani-Tabari, Jae Jin Song, Xiling Yin, Senthilkumar S. Karuppagounder, George K. Umanah, A. V.Subba Rao, Yu Ree Choi, Akanksha Aggarwal, Sohyun Chang, Hyunhee Kim, Jiyoung Byun, Jun O. Liu, Ted M. Dawson, Valina L. Dawson

School of Medicine

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

Abstract

Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that acts as a final executioner in parthanatos. PAAN's role in Parkinson's disease (PD) and whether it is amenable to chemical inhibition is not known. Here, we show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.

Original language	English (US)
Pages (from-to)	1943-1959.e21
Journal	Cell
Volume	185
Issue number	11
DOIs	https://doi.org/10.1016/j.cell.2022.04.020
State	Published - May 26 2022

Keywords

MIF
PARP1
Parkinson's disease
cell death
neurodegeneration
parthanatos
synuclein

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2022.04.020

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Park, H., Kam, T. I., Peng, H., Chou, S. C., Mehrabani-Tabari, A. A., Song, J. J., Yin, X., Karuppagounder, S. S., Umanah, G. K., Rao, A. V. S., Choi, Y. R., Aggarwal, A., Chang, S., Kim, H., Byun, J., Liu, J. O., Dawson, T. M., & Dawson, V. L. (2022). PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease. Cell, 185(11), 1943-1959.e21. https://doi.org/10.1016/j.cell.2022.04.020

Park, H, Kam, TI, Peng, H, Chou, SC, Mehrabani-Tabari, AA, Song, JJ, Yin, X, Karuppagounder, SS, Umanah, GK, Rao, AVS, Choi, YR, Aggarwal, A, Chang, S, Kim, H, Byun, J, Liu, JO , Dawson, TM & Dawson, VL 2022, 'PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease', Cell, vol. 185, no. 11, pp. 1943-1959.e21. https://doi.org/10.1016/j.cell.2022.04.020

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title = "PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease",

abstract = "Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that acts as a final executioner in parthanatos. PAAN's role in Parkinson's disease (PD) and whether it is amenable to chemical inhibition is not known. Here, we show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.",

keywords = "MIF, PARP1, Parkinson's disease, cell death, neurodegeneration, parthanatos, synuclein",

author = "Hyejin Park and Kam, {Tae In} and Hanjing Peng and Chou, {Shih Ching} and Mehrabani-Tabari, {Amir A.} and Song, {Jae Jin} and Xiling Yin and Karuppagounder, {Senthilkumar S.} and Umanah, {George K.} and Rao, {A. V.Subba} and Choi, {Yu Ree} and Akanksha Aggarwal and Sohyun Chang and Hyunhee Kim and Jiyoung Byun and Liu, {Jun O.} and Dawson, {Ted M.} and Dawson, {Valina L.}",

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year = "2022",

month = may,

day = "26",

doi = "10.1016/j.cell.2022.04.020",

language = "English (US)",

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T1 - PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease

AU - Park, Hyejin

AU - Kam, Tae In

AU - Peng, Hanjing

AU - Chou, Shih Ching

AU - Mehrabani-Tabari, Amir A.

AU - Song, Jae Jin

AU - Yin, Xiling

AU - Karuppagounder, Senthilkumar S.

AU - Umanah, George K.

AU - Rao, A. V.Subba

AU - Choi, Yu Ree

AU - Aggarwal, Akanksha

AU - Chang, Sohyun

AU - Kim, Hyunhee

AU - Byun, Jiyoung

AU - Liu, Jun O.

AU - Dawson, Ted M.

AU - Dawson, Valina L.

PY - 2022/5/26

Y1 - 2022/5/26

N2 - Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that acts as a final executioner in parthanatos. PAAN's role in Parkinson's disease (PD) and whether it is amenable to chemical inhibition is not known. Here, we show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.

AB - Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that acts as a final executioner in parthanatos. PAAN's role in Parkinson's disease (PD) and whether it is amenable to chemical inhibition is not known. Here, we show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.

KW - MIF

KW - PARP1

KW - Parkinson's disease

KW - cell death

KW - neurodegeneration

KW - parthanatos

KW - synuclein

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SP - 1943-1959.e21

JO - Cell

JF - Cell

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ER -

PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease

Abstract

Keywords

ASJC Scopus subject areas

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