Initiation of Parkinson’s disease from gut to brain by δ-secretase

Eun Hee Ahn; Seong Su Kang; Xia Liu; Guiqin Chen; Zhentao Zhang; Bindu Chandrasekharan; Ashfaqul M. Alam; Andrew S. Neish; Xuebing Cao; Keqiang Ye

doi:10.1038/s41422-019-0241-9

Initiation of Parkinson’s disease from gut to brain by δ-secretase

Eun Hee Ahn, Seong Su Kang, Xia Liu, Guiqin Chen, Zhentao Zhang, Bindu Chandrasekharan, Ashfaqul M. Alam, Andrew S. Neish, Xuebing Cao, Keqiang Ye

Microbiology, Immunology, and Molecular Genetics

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

55 Scopus citations

Abstract

Lewy pathology, composed of α-Synuclein (α-Syn) inclusions, a hallmark of Parkinson’s disease (PD), progressively spreads from the enteric nervous system (ENS) to the central nervous system (CNS). However, it remains unclear how this process is regulated at a molecular level. Here we show that δ-secretase (asparagine endopeptidase, AEP) cleaves both α-Syn at N103 and Tau at N368, and mediates their fibrillization and retrograde propagation from the gut to the brain, triggering nigra dopaminergic neuronal loss associated with Lewy bodies and motor dysfunction. α-Syn N103 and Tau N368 robustly interact with each other and are highly elevated in PD patients’ gut and brain. Chronic oral administration of the neurotoxin rotenone induces AEP activation and α-Syn N103/Tau N368 complex formation in the gut, eliciting constipation and dopaminergic neuronal death in an AEP-dependent manner. Preformed fibrils (PFFs) of α-Syn N103/Tau N368 are more neurotoxic and compact, and aggregate more quickly along the vagus nerve than their FL/FL counterparts or the individual fragments’ fibrils. Colonic injection of PFFs induces PD pathologies, motor dysfunctions, and cognitive impairments. Thus, δ-secretase plays a crucial role in initiating PD pathology progression from the ENS to the CNS.

Original language	English
Pages (from-to)	70-87
Number of pages	18
Journal	Cell Research
Volume	30
Issue number	1
DOIs	https://doi.org/10.1038/s41422-019-0241-9
State	Published - Jan 1 2020

Bibliographical note

Funding Information:
We thank ADRC at Emory University for human AD patients and healthy control samples. This work was supported by grants from NIH RF1 (AG051538) to K.Y. HPLC analysis was supported in part by the Emory HPLC Bioanalytical Core (EHBC), which was supported by the Department of Pharmacology, Emory University School of Medicine and the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.

Publisher Copyright:
© 2019, IBCB, SIBS, CAS.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1038/s41422-019-0241-9

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title = "Initiation of Parkinson{\textquoteright}s disease from gut to brain by δ-secretase",

abstract = "Lewy pathology, composed of α-Synuclein (α-Syn) inclusions, a hallmark of Parkinson{\textquoteright}s disease (PD), progressively spreads from the enteric nervous system (ENS) to the central nervous system (CNS). However, it remains unclear how this process is regulated at a molecular level. Here we show that δ-secretase (asparagine endopeptidase, AEP) cleaves both α-Syn at N103 and Tau at N368, and mediates their fibrillization and retrograde propagation from the gut to the brain, triggering nigra dopaminergic neuronal loss associated with Lewy bodies and motor dysfunction. α-Syn N103 and Tau N368 robustly interact with each other and are highly elevated in PD patients{\textquoteright} gut and brain. Chronic oral administration of the neurotoxin rotenone induces AEP activation and α-Syn N103/Tau N368 complex formation in the gut, eliciting constipation and dopaminergic neuronal death in an AEP-dependent manner. Preformed fibrils (PFFs) of α-Syn N103/Tau N368 are more neurotoxic and compact, and aggregate more quickly along the vagus nerve than their FL/FL counterparts or the individual fragments{\textquoteright} fibrils. Colonic injection of PFFs induces PD pathologies, motor dysfunctions, and cognitive impairments. Thus, δ-secretase plays a crucial role in initiating PD pathology progression from the ENS to the CNS.",

author = "Ahn, {Eun Hee} and Kang, {Seong Su} and Xia Liu and Guiqin Chen and Zhentao Zhang and Bindu Chandrasekharan and Alam, {Ashfaqul M.} and Neish, {Andrew S.} and Xuebing Cao and Keqiang Ye",

note = "Funding Information: We thank ADRC at Emory University for human AD patients and healthy control samples. This work was supported by grants from NIH RF1 (AG051538) to K.Y. HPLC analysis was supported in part by the Emory HPLC Bioanalytical Core (EHBC), which was supported by the Department of Pharmacology, Emory University School of Medicine and the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2019, IBCB, SIBS, CAS.",

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AU - Ahn, Eun Hee

AU - Kang, Seong Su

AU - Liu, Xia

AU - Chen, Guiqin

AU - Zhang, Zhentao

AU - Chandrasekharan, Bindu

AU - Alam, Ashfaqul M.

AU - Neish, Andrew S.

AU - Cao, Xuebing

AU - Ye, Keqiang

N1 - Funding Information: We thank ADRC at Emory University for human AD patients and healthy control samples. This work was supported by grants from NIH RF1 (AG051538) to K.Y. HPLC analysis was supported in part by the Emory HPLC Bioanalytical Core (EHBC), which was supported by the Department of Pharmacology, Emory University School of Medicine and the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. Publisher Copyright: © 2019, IBCB, SIBS, CAS.

PY - 2020/1/1

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N2 - Lewy pathology, composed of α-Synuclein (α-Syn) inclusions, a hallmark of Parkinson’s disease (PD), progressively spreads from the enteric nervous system (ENS) to the central nervous system (CNS). However, it remains unclear how this process is regulated at a molecular level. Here we show that δ-secretase (asparagine endopeptidase, AEP) cleaves both α-Syn at N103 and Tau at N368, and mediates their fibrillization and retrograde propagation from the gut to the brain, triggering nigra dopaminergic neuronal loss associated with Lewy bodies and motor dysfunction. α-Syn N103 and Tau N368 robustly interact with each other and are highly elevated in PD patients’ gut and brain. Chronic oral administration of the neurotoxin rotenone induces AEP activation and α-Syn N103/Tau N368 complex formation in the gut, eliciting constipation and dopaminergic neuronal death in an AEP-dependent manner. Preformed fibrils (PFFs) of α-Syn N103/Tau N368 are more neurotoxic and compact, and aggregate more quickly along the vagus nerve than their FL/FL counterparts or the individual fragments’ fibrils. Colonic injection of PFFs induces PD pathologies, motor dysfunctions, and cognitive impairments. Thus, δ-secretase plays a crucial role in initiating PD pathology progression from the ENS to the CNS.

AB - Lewy pathology, composed of α-Synuclein (α-Syn) inclusions, a hallmark of Parkinson’s disease (PD), progressively spreads from the enteric nervous system (ENS) to the central nervous system (CNS). However, it remains unclear how this process is regulated at a molecular level. Here we show that δ-secretase (asparagine endopeptidase, AEP) cleaves both α-Syn at N103 and Tau at N368, and mediates their fibrillization and retrograde propagation from the gut to the brain, triggering nigra dopaminergic neuronal loss associated with Lewy bodies and motor dysfunction. α-Syn N103 and Tau N368 robustly interact with each other and are highly elevated in PD patients’ gut and brain. Chronic oral administration of the neurotoxin rotenone induces AEP activation and α-Syn N103/Tau N368 complex formation in the gut, eliciting constipation and dopaminergic neuronal death in an AEP-dependent manner. Preformed fibrils (PFFs) of α-Syn N103/Tau N368 are more neurotoxic and compact, and aggregate more quickly along the vagus nerve than their FL/FL counterparts or the individual fragments’ fibrils. Colonic injection of PFFs induces PD pathologies, motor dysfunctions, and cognitive impairments. Thus, δ-secretase plays a crucial role in initiating PD pathology progression from the ENS to the CNS.

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JF - Cell Research

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Initiation of Parkinson’s disease from gut to brain by δ-secretase

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