Targeted overexpression of the parkin substrate Pael-R in the nigrostriatal system of adult rats to model Parkinson's disease
Loss of function of parkin, an ubiquitin ligase, is responsible for autosomal recessive juvenile parkinsonism (AR-JP). Parkin-associated endothelin receptor-like receptor (Pael-R) was identified as an authentic substrate of parkin and is thought to accumulate abnormally following loss of parkin acti...
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doaj-84ce233a35bb4ffb909056e2c1189b602021-03-20T04:57:26ZengElsevierNeurobiology of Disease1095-953X2009-07-013513241Targeted overexpression of the parkin substrate Pael-R in the nigrostriatal system of adult rats to model Parkinson's diseaseJulien Dusonchet0Jean-Charles Bensadoun1Bernard L. Schneider2Patrick Aebischer3Ecole Polytechnique Fédérale de Lausanne, Brain Mind Institute, EPFL SV BMI LEN, AI 1207, Station 15, CH-1015 Lausanne, SwitzerlandEcole Polytechnique Fédérale de Lausanne, Brain Mind Institute, EPFL SV BMI LEN, AI 1207, Station 15, CH-1015 Lausanne, SwitzerlandEcole Polytechnique Fédérale de Lausanne, Brain Mind Institute, EPFL SV BMI LEN, AI 1207, Station 15, CH-1015 Lausanne, SwitzerlandCorresponding author. Fax: +41 21 693 95 20.; Ecole Polytechnique Fédérale de Lausanne, Brain Mind Institute, EPFL SV BMI LEN, AI 1207, Station 15, CH-1015 Lausanne, SwitzerlandLoss of function of parkin, an ubiquitin ligase, is responsible for autosomal recessive juvenile parkinsonism (AR-JP). Parkin-associated endothelin receptor-like receptor (Pael-R) was identified as an authentic substrate of parkin and is thought to accumulate abnormally following loss of parkin activity, causing neurodegeneration of nigral dopaminergic neurons in AR-JP patients. Our aim is therefore to generate a model of AR-JP through overexpression of Pael-R in the nigrostriatal system of adult rats. Using recombinant adeno-associated virus pseudotyped with the serotype 6 capsid (rAAV2/6) as a gene delivery tool, we achieved targeted and robust overexpression of rat Pael-R in nigral neurons and their striatal terminals. Overexpressed Pael-R was shown to accumulate very rapidly in an insoluble form. Accumulation of the receptor triggered a rapid and severe loss of nigral neurons and nigrostriatal fibers and terminals. No cell recovery was observed for up to 6 months post-injection. GABAergic neurons of the globus pallidus were unaffected by Pael-R overexpression, highlighting the selective vulnerability of nigral dopaminergic neurons to abnormal levels of Pael-R. Pael-R-induced degeneration also led to a depletion of striatal dopamine resulting in spontaneous motor impairments, as measured in the cylinder and stepping tests for forelimb akinesia. Interestingly, behavioral deficits of individual animals were correlated with the extent of the nigrostriatal lesion. Insoluble accumulation of Pael-R in the nigrostriatal system of adult rats represents, therefore, a chronic, rapidly progressing and specific model of AR-JP, which recapitulates major pathological hallmarks of the disease.http://www.sciencedirect.com/science/article/pii/S0969996109000758Parkinson's diseaseAutosomal-recessive juvenile parkinsonismAdeno-associated viral vectorParkin-associated endothelin receptor-like receptorInsoluble accumulationNeurodegeneration |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Julien Dusonchet Jean-Charles Bensadoun Bernard L. Schneider Patrick Aebischer |
spellingShingle |
Julien Dusonchet Jean-Charles Bensadoun Bernard L. Schneider Patrick Aebischer Targeted overexpression of the parkin substrate Pael-R in the nigrostriatal system of adult rats to model Parkinson's disease Neurobiology of Disease Parkinson's disease Autosomal-recessive juvenile parkinsonism Adeno-associated viral vector Parkin-associated endothelin receptor-like receptor Insoluble accumulation Neurodegeneration |
author_facet |
Julien Dusonchet Jean-Charles Bensadoun Bernard L. Schneider Patrick Aebischer |
author_sort |
Julien Dusonchet |
title |
Targeted overexpression of the parkin substrate Pael-R in the nigrostriatal system of adult rats to model Parkinson's disease |
title_short |
Targeted overexpression of the parkin substrate Pael-R in the nigrostriatal system of adult rats to model Parkinson's disease |
title_full |
Targeted overexpression of the parkin substrate Pael-R in the nigrostriatal system of adult rats to model Parkinson's disease |
title_fullStr |
Targeted overexpression of the parkin substrate Pael-R in the nigrostriatal system of adult rats to model Parkinson's disease |
title_full_unstemmed |
Targeted overexpression of the parkin substrate Pael-R in the nigrostriatal system of adult rats to model Parkinson's disease |
title_sort |
targeted overexpression of the parkin substrate pael-r in the nigrostriatal system of adult rats to model parkinson's disease |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2009-07-01 |
description |
Loss of function of parkin, an ubiquitin ligase, is responsible for autosomal recessive juvenile parkinsonism (AR-JP). Parkin-associated endothelin receptor-like receptor (Pael-R) was identified as an authentic substrate of parkin and is thought to accumulate abnormally following loss of parkin activity, causing neurodegeneration of nigral dopaminergic neurons in AR-JP patients. Our aim is therefore to generate a model of AR-JP through overexpression of Pael-R in the nigrostriatal system of adult rats. Using recombinant adeno-associated virus pseudotyped with the serotype 6 capsid (rAAV2/6) as a gene delivery tool, we achieved targeted and robust overexpression of rat Pael-R in nigral neurons and their striatal terminals. Overexpressed Pael-R was shown to accumulate very rapidly in an insoluble form. Accumulation of the receptor triggered a rapid and severe loss of nigral neurons and nigrostriatal fibers and terminals. No cell recovery was observed for up to 6 months post-injection. GABAergic neurons of the globus pallidus were unaffected by Pael-R overexpression, highlighting the selective vulnerability of nigral dopaminergic neurons to abnormal levels of Pael-R. Pael-R-induced degeneration also led to a depletion of striatal dopamine resulting in spontaneous motor impairments, as measured in the cylinder and stepping tests for forelimb akinesia. Interestingly, behavioral deficits of individual animals were correlated with the extent of the nigrostriatal lesion. Insoluble accumulation of Pael-R in the nigrostriatal system of adult rats represents, therefore, a chronic, rapidly progressing and specific model of AR-JP, which recapitulates major pathological hallmarks of the disease. |
topic |
Parkinson's disease Autosomal-recessive juvenile parkinsonism Adeno-associated viral vector Parkin-associated endothelin receptor-like receptor Insoluble accumulation Neurodegeneration |
url |
http://www.sciencedirect.com/science/article/pii/S0969996109000758 |
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