Nigrostriatal 6-hydroxydopamine lesions increase alpha-synuclein levels and permeability in rat colon

Hengjing Cui; Joshua D Elford; Okko Alitalo; Paula Perez-Pardo; Janne Tampio; Kristiina M Huttunen; Aletta Kraneveld; Markus M Forsberg; Timo T Myöhänen; Aaro J Jalkanen

doi:10.1016/j.neurobiolaging.2023.05.007

Nigrostriatal 6-hydroxydopamine lesions increase alpha-synuclein levels and permeability in rat colon

Hengjing Cui, Joshua D Elford, Okko Alitalo, Paula Perez-Pardo, Janne Tampio, Kristiina M Huttunen, Aletta Kraneveld, Markus M Forsberg, Timo T Myöhänen, Aaro J Jalkanen

Faculty of Science

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Increasing evidence suggests that the gut-brain axis plays a crucial role in Parkinson's disease (PD). The abnormal accumulation of aggregated alpha-synuclein (aSyn) in the brain is a key pathological feature of PD. Intracerebral 6-hydroxydopamine (6-OHDA) is a widely used dopaminergic lesion model of PD. It exerts no aSyn pathology in the brain, but changes in the gut have not been assessed. Here, 6-OHDA was administered unilaterally either to the rat medial forebrain bundle (MFB) or striatum. Increased levels of glial fibrillary acidic protein in the ileum and colon were detected at 5 weeks postlesion. 6-OHDA decreased the Zonula occludens protein 1 barrier integrity score, suggesting increased colonic permeability. The total aSyn and Ser129 phosphorylated aSyn levels were elevated in the colon after the MFB lesion. Both lesions generally increased the total aSyn, pS129 aSyn, and ionized calcium-binding adapter molecule 1 (Iba1) levels in the lesioned striatum. In conclusion, 6-OHDA-induced nigrostriatal dopaminergic damage leads to increased aSyn levels and glial cell activation particularly in the colon, suggesting that the gut-brain axis interactions in PD are bidirectional and the detrimental process may start in the brain.

Original language	English
Pages (from-to)	62-71
Number of pages	10
Journal	Neurobiology of Aging
Volume	129
DOIs	https://doi.org/10.1016/j.neurobiolaging.2023.05.007
Publication status	Published - Sept 2023

Bibliographical note

Funding

This study was financially supported by the School of Pharmacy, University of Eastern Finland (NFG grant for AJJ), and by Sigrid Jusélius Foundation (for TTM). The funding source had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Dr. Ewen MacDonald is acknowledged for revising the language of the manuscript.

Funders	Funder number
NFG
Itä-Suomen Yliopisto
Sigrid Juséliuksen Säätiö

Keywords

Rats
Animals
Oxidopamine
alpha-Synuclein/metabolism
Parkinson Disease/metabolism
Brain/metabolism
Dopamine/metabolism
Colon/metabolism

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title = "Nigrostriatal 6-hydroxydopamine lesions increase alpha-synuclein levels and permeability in rat colon",

abstract = "Increasing evidence suggests that the gut-brain axis plays a crucial role in Parkinson's disease (PD). The abnormal accumulation of aggregated alpha-synuclein (aSyn) in the brain is a key pathological feature of PD. Intracerebral 6-hydroxydopamine (6-OHDA) is a widely used dopaminergic lesion model of PD. It exerts no aSyn pathology in the brain, but changes in the gut have not been assessed. Here, 6-OHDA was administered unilaterally either to the rat medial forebrain bundle (MFB) or striatum. Increased levels of glial fibrillary acidic protein in the ileum and colon were detected at 5 weeks postlesion. 6-OHDA decreased the Zonula occludens protein 1 barrier integrity score, suggesting increased colonic permeability. The total aSyn and Ser129 phosphorylated aSyn levels were elevated in the colon after the MFB lesion. Both lesions generally increased the total aSyn, pS129 aSyn, and ionized calcium-binding adapter molecule 1 (Iba1) levels in the lesioned striatum. In conclusion, 6-OHDA-induced nigrostriatal dopaminergic damage leads to increased aSyn levels and glial cell activation particularly in the colon, suggesting that the gut-brain axis interactions in PD are bidirectional and the detrimental process may start in the brain.",

keywords = "Rats, Animals, Oxidopamine, alpha-Synuclein/metabolism, Parkinson Disease/metabolism, Brain/metabolism, Dopamine/metabolism, Colon/metabolism",

author = "Hengjing Cui and Elford, {Joshua D} and Okko Alitalo and Paula Perez-Pardo and Janne Tampio and Huttunen, {Kristiina M} and Aletta Kraneveld and Forsberg, {Markus M} and My{\"o}h{\"a}nen, {Timo T} and Jalkanen, {Aaro J}",

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doi = "10.1016/j.neurobiolaging.2023.05.007",

language = "English",

volume = "129",

pages = "62--71",

journal = "Neurobiology of Aging",

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publisher = "Elsevier Inc.",

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T1 - Nigrostriatal 6-hydroxydopamine lesions increase alpha-synuclein levels and permeability in rat colon

AU - Cui, Hengjing

AU - Elford, Joshua D

AU - Alitalo, Okko

AU - Perez-Pardo, Paula

AU - Tampio, Janne

AU - Huttunen, Kristiina M

AU - Kraneveld, Aletta

AU - Forsberg, Markus M

AU - Myöhänen, Timo T

AU - Jalkanen, Aaro J

PY - 2023/9

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N2 - Increasing evidence suggests that the gut-brain axis plays a crucial role in Parkinson's disease (PD). The abnormal accumulation of aggregated alpha-synuclein (aSyn) in the brain is a key pathological feature of PD. Intracerebral 6-hydroxydopamine (6-OHDA) is a widely used dopaminergic lesion model of PD. It exerts no aSyn pathology in the brain, but changes in the gut have not been assessed. Here, 6-OHDA was administered unilaterally either to the rat medial forebrain bundle (MFB) or striatum. Increased levels of glial fibrillary acidic protein in the ileum and colon were detected at 5 weeks postlesion. 6-OHDA decreased the Zonula occludens protein 1 barrier integrity score, suggesting increased colonic permeability. The total aSyn and Ser129 phosphorylated aSyn levels were elevated in the colon after the MFB lesion. Both lesions generally increased the total aSyn, pS129 aSyn, and ionized calcium-binding adapter molecule 1 (Iba1) levels in the lesioned striatum. In conclusion, 6-OHDA-induced nigrostriatal dopaminergic damage leads to increased aSyn levels and glial cell activation particularly in the colon, suggesting that the gut-brain axis interactions in PD are bidirectional and the detrimental process may start in the brain.

AB - Increasing evidence suggests that the gut-brain axis plays a crucial role in Parkinson's disease (PD). The abnormal accumulation of aggregated alpha-synuclein (aSyn) in the brain is a key pathological feature of PD. Intracerebral 6-hydroxydopamine (6-OHDA) is a widely used dopaminergic lesion model of PD. It exerts no aSyn pathology in the brain, but changes in the gut have not been assessed. Here, 6-OHDA was administered unilaterally either to the rat medial forebrain bundle (MFB) or striatum. Increased levels of glial fibrillary acidic protein in the ileum and colon were detected at 5 weeks postlesion. 6-OHDA decreased the Zonula occludens protein 1 barrier integrity score, suggesting increased colonic permeability. The total aSyn and Ser129 phosphorylated aSyn levels were elevated in the colon after the MFB lesion. Both lesions generally increased the total aSyn, pS129 aSyn, and ionized calcium-binding adapter molecule 1 (Iba1) levels in the lesioned striatum. In conclusion, 6-OHDA-induced nigrostriatal dopaminergic damage leads to increased aSyn levels and glial cell activation particularly in the colon, suggesting that the gut-brain axis interactions in PD are bidirectional and the detrimental process may start in the brain.

KW - Rats

KW - Animals

KW - Oxidopamine

KW - alpha-Synuclein/metabolism

KW - Parkinson Disease/metabolism

KW - Brain/metabolism

KW - Dopamine/metabolism

KW - Colon/metabolism

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VL - 129

SP - 62

EP - 71

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

Nigrostriatal 6-hydroxydopamine lesions increase alpha-synuclein levels and permeability in rat colon

Abstract

Bibliographical note

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Keywords

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