Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease

Yun Yang; Victor Tapias; Diana Acosta; Hui Xu; Huanlian Chen; Ruchika Bhawal; Elizabeth T. Anderson; Elena Ivanova; Hening Lin; Botir T. Sagdullaev; Jianer Chen; William L. Klein; Kirsten L. Viola; Sam Gandy; Vahram Haroutunian; M. Flint Beal; David Eliezer; Sheng Zhang; Gary E. Gibson

doi:10.1038/s41467-021-27572-2

Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease

Yun Yang, Victor Tapias, Diana Acosta, Hui Xu, Huanlian Chen, Ruchika Bhawal, Elizabeth T. Anderson, Elena Ivanova, Hening Lin, Botir T. Sagdullaev, Jianer Chen, William L. Klein, Kirsten L. Viola, Sam Gandy, Vahram Haroutunian, M. Flint Beal, David Eliezer, Sheng Zhang, Gary E. Gibson^*

^*Corresponding author for this work

Neurobiology

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

63 Scopus citations

Abstract

Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer’s disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.

Original language	English (US)
Article number	159
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27572-2
State	Published - Dec 2022

Funding

The studies were supported by: NIH-NIA grants P01AG014930 (G.E.G., M.F.B., and S.Z.) and R37AG019391 (D.E.); R01-EY026576 and R01-EY029796 (B.T.S.); NIH SIG 1S10 OD017992-01 (S.Z.); HHSN271201300031C (V.H.); AG18877 & AG22547 (W.L.K.); AG059319 and AG058469 (S.G.); AG005138 and AG066514 (to Mary Sano); R37AG019391 and RF1AG066493 (D.E.) and F31AG069416 (D.A.); S10OD016320 (William Clay Bracken, director of WCM NMR facility) Burke Neurological Institute, Weill Cornell Medicine; Zhejiang Provincial Natural Science Foundation of China LGF21H090018 (Y.Y.); Integrated Medicine Research Center for Neurological Rehabilitation, College of Medicine, Jiaxing University, Jiaxing, China (Dean J. Chen). We thank L. Cohen-Gould, MS, director of the Microscopy and Image Analysis Core Facility (Weill Cornell Medicine) for the EM and C. Bracken, PhD, director of the NMR Facility (Weill Cornell Medicine) for help with NMR experiments. We thank E. Ivanova and Structural and Functional Imaging Core at the Burke Neurological Institute for the technical assistance. We are grateful to the NIH Neurobiobank for providing the carefully characterized human brains. We thank Dr. R. Kayed (Department Neurology, University of Texas Medical Branch) for kindly providing the T22 antibody for tau aggregates. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD015124. For public access by webpage: http://www.ebi.ac.uk/pride/archive/projects/PXD015124 and for FTP download: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/12/PXD015124.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Yang, Y., Tapias, V., Acosta, D., Xu, H., Chen, H., Bhawal, R., Anderson, E. T., Ivanova, E., Lin, H., Sagdullaev, B. T., Chen, J., Klein, W. L., Viola, K. L., Gandy, S., Haroutunian, V., Beal, M. F., Eliezer, D., Zhang, S., & Gibson, G. E. (2022). Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease. Nature communications, 13(1), Article 159. https://doi.org/10.1038/s41467-021-27572-2

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title = "Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer{\textquoteright}s disease",

abstract = "Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer{\textquoteright}s disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.",

author = "Yun Yang and Victor Tapias and Diana Acosta and Hui Xu and Huanlian Chen and Ruchika Bhawal and Anderson, {Elizabeth T.} and Elena Ivanova and Hening Lin and Sagdullaev, {Botir T.} and Jianer Chen and Klein, {William L.} and Viola, {Kirsten L.} and Sam Gandy and Vahram Haroutunian and Beal, {M. Flint} and David Eliezer and Sheng Zhang and Gibson, {Gary E.}",

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year = "2022",

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doi = "10.1038/s41467-021-27572-2",

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Yang, Y, Tapias, V, Acosta, D, Xu, H, Chen, H, Bhawal, R, Anderson, ET, Ivanova, E, Lin, H, Sagdullaev, BT, Chen, J, Klein, WL, Viola, KL, Gandy, S, Haroutunian, V, Beal, MF, Eliezer, D, Zhang, S & Gibson, GE 2022, 'Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease', Nature communications, vol. 13, no. 1, 159. https://doi.org/10.1038/s41467-021-27572-2

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T1 - Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease

AU - Yang, Yun

AU - Tapias, Victor

AU - Acosta, Diana

AU - Xu, Hui

AU - Chen, Huanlian

AU - Bhawal, Ruchika

AU - Anderson, Elizabeth T.

AU - Ivanova, Elena

AU - Lin, Hening

AU - Sagdullaev, Botir T.

AU - Chen, Jianer

AU - Klein, William L.

AU - Viola, Kirsten L.

AU - Gandy, Sam

AU - Haroutunian, Vahram

AU - Beal, M. Flint

AU - Eliezer, David

AU - Zhang, Sheng

AU - Gibson, Gary E.

PY - 2022/12

Y1 - 2022/12

N2 - Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer’s disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.

AB - Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer’s disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.

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Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease

Abstract

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