Targeted deletion of the aquaglyceroporin AQP9 is protective in a mouse model of Parkinson's disease.
More than 90% of the cases of Parkinson's disease have unknown etiology. Gradual loss of dopaminergic neurons of substantia nigra is the main cause of morbidity in this disease. External factors such as environmental toxins are believed to play a role in the cell loss, although the cause of the...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5864064?pdf=render |
| _version_ | 1819268018477203456 |
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| author | Katja Stahl Soulmaz Rahmani Agnete Prydz Nadia Skauli Nanna MacAulay Maria N Mylonakou Reidun Torp Øivind Skare Torill Berg Trygve B Leergaard Ragnhild E Paulsen Ole P Ottersen Mahmood Amiry-Moghaddam |
| author_facet | Katja Stahl Soulmaz Rahmani Agnete Prydz Nadia Skauli Nanna MacAulay Maria N Mylonakou Reidun Torp Øivind Skare Torill Berg Trygve B Leergaard Ragnhild E Paulsen Ole P Ottersen Mahmood Amiry-Moghaddam |
| author_sort | Katja Stahl |
| collection | DOAJ |
| description | More than 90% of the cases of Parkinson's disease have unknown etiology. Gradual loss of dopaminergic neurons of substantia nigra is the main cause of morbidity in this disease. External factors such as environmental toxins are believed to play a role in the cell loss, although the cause of the selective vulnerability of dopaminergic neurons remains unknown. We have previously shown that aquaglyceroporin AQP9 is expressed in dopaminergic neurons and astrocytes of rodent brain. AQP9 is permeable to a broad spectrum of substrates including purines, pyrimidines, and lactate, in addition to water and glycerol. Here we test our hypothesis that AQP9 serves as an influx route for exogenous toxins and, hence, may contribute to the selective vulnerability of nigral dopaminergic (tyrosine hydroxylase-positive) neurons. Using Xenopus oocytes injected with Aqp9 cRNA, we show that AQP9 is permeable to the parkinsonogenic toxin 1-methyl-4-phenylpyridinium (MPP+). Stable expression of AQP9 in HEK cells increases their vulnerability to MPP+ and to arsenite-another parkinsonogenic toxin. Conversely, targeted deletion of Aqp9 in mice protects nigral dopaminergic neurons against MPP+ toxicity. A protective effect of Aqp9 deletion was demonstrated in organotypic slice cultures of mouse midbrain exposed to MPP+ in vitro and in mice subjected to intrastriatal injections of MPP+ in vivo. Seven days after intrastriatal MPP+ injections, the population of tyrosine hydroxylase-positive cells in substantia nigra is reduced by 48% in Aqp9 knockout mice compared with 67% in WT littermates. Our results show that AQP9 -selectively expressed in catecholaminergic neurons-is permeable to MPP+ and suggest that this aquaglyceroporin contributes to the selective vulnerability of nigral dopaminergic neurons by providing an entry route for parkinsonogenic toxins. To our knowledge this is the first evidence implicating a toxin permeable membrane channel in the pathophysiology of Parkinson's disease. |
| first_indexed | 2024-12-23T21:26:23Z |
| format | Article |
| id | doaj.art-17e2d1656dc043a689dab31d9bf5d0dc |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T21:26:23Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-17e2d1656dc043a689dab31d9bf5d0dc2022-12-21T17:30:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01133e019489610.1371/journal.pone.0194896Targeted deletion of the aquaglyceroporin AQP9 is protective in a mouse model of Parkinson's disease.Katja StahlSoulmaz RahmaniAgnete PrydzNadia SkauliNanna MacAulayMaria N MylonakouReidun TorpØivind SkareTorill BergTrygve B LeergaardRagnhild E PaulsenOle P OttersenMahmood Amiry-MoghaddamMore than 90% of the cases of Parkinson's disease have unknown etiology. Gradual loss of dopaminergic neurons of substantia nigra is the main cause of morbidity in this disease. External factors such as environmental toxins are believed to play a role in the cell loss, although the cause of the selective vulnerability of dopaminergic neurons remains unknown. We have previously shown that aquaglyceroporin AQP9 is expressed in dopaminergic neurons and astrocytes of rodent brain. AQP9 is permeable to a broad spectrum of substrates including purines, pyrimidines, and lactate, in addition to water and glycerol. Here we test our hypothesis that AQP9 serves as an influx route for exogenous toxins and, hence, may contribute to the selective vulnerability of nigral dopaminergic (tyrosine hydroxylase-positive) neurons. Using Xenopus oocytes injected with Aqp9 cRNA, we show that AQP9 is permeable to the parkinsonogenic toxin 1-methyl-4-phenylpyridinium (MPP+). Stable expression of AQP9 in HEK cells increases their vulnerability to MPP+ and to arsenite-another parkinsonogenic toxin. Conversely, targeted deletion of Aqp9 in mice protects nigral dopaminergic neurons against MPP+ toxicity. A protective effect of Aqp9 deletion was demonstrated in organotypic slice cultures of mouse midbrain exposed to MPP+ in vitro and in mice subjected to intrastriatal injections of MPP+ in vivo. Seven days after intrastriatal MPP+ injections, the population of tyrosine hydroxylase-positive cells in substantia nigra is reduced by 48% in Aqp9 knockout mice compared with 67% in WT littermates. Our results show that AQP9 -selectively expressed in catecholaminergic neurons-is permeable to MPP+ and suggest that this aquaglyceroporin contributes to the selective vulnerability of nigral dopaminergic neurons by providing an entry route for parkinsonogenic toxins. To our knowledge this is the first evidence implicating a toxin permeable membrane channel in the pathophysiology of Parkinson's disease.http://europepmc.org/articles/PMC5864064?pdf=render |
| spellingShingle | Katja Stahl Soulmaz Rahmani Agnete Prydz Nadia Skauli Nanna MacAulay Maria N Mylonakou Reidun Torp Øivind Skare Torill Berg Trygve B Leergaard Ragnhild E Paulsen Ole P Ottersen Mahmood Amiry-Moghaddam Targeted deletion of the aquaglyceroporin AQP9 is protective in a mouse model of Parkinson's disease. PLoS ONE |
| title | Targeted deletion of the aquaglyceroporin AQP9 is protective in a mouse model of Parkinson's disease. |
| title_full | Targeted deletion of the aquaglyceroporin AQP9 is protective in a mouse model of Parkinson's disease. |
| title_fullStr | Targeted deletion of the aquaglyceroporin AQP9 is protective in a mouse model of Parkinson's disease. |
| title_full_unstemmed | Targeted deletion of the aquaglyceroporin AQP9 is protective in a mouse model of Parkinson's disease. |
| title_short | Targeted deletion of the aquaglyceroporin AQP9 is protective in a mouse model of Parkinson's disease. |
| title_sort | targeted deletion of the aquaglyceroporin aqp9 is protective in a mouse model of parkinson s disease |
| url | http://europepmc.org/articles/PMC5864064?pdf=render |
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