Modeling pathophysiological aspects of Parkinson’s disease: Manipulating DA handling and alpha-synuclein expression in the nigrostriatal pathway using viral vectors
(2010) In Lund University Faculty of Medicine Doctoral Dissertation Series 2010:61.- Abstract
- The pathological hallmark of Parkinson’s disease is dopaminergic neurodegeneration in the substantia nigra
pars compacta neurons and accumulation of α-synuclein containing aggregates in the surviving neurons. The
cause of cell death in Parkinson’s disease and the involvement of α-synuclein in the pathophysiology of the
disease are unknown. Although other neuronal cell types exhibit α-synuclein positive aggregates, substantia
nigra dopamine neurons display a selective vulnerability to α-synuclein mediated neurodegeneration. In this
thesis work I have focused on the possible mechanisms underlying the vulnerability of dopamine producing
neurons against α-synuclein induced neurotoxicity. To... (More) - The pathological hallmark of Parkinson’s disease is dopaminergic neurodegeneration in the substantia nigra
pars compacta neurons and accumulation of α-synuclein containing aggregates in the surviving neurons. The
cause of cell death in Parkinson’s disease and the involvement of α-synuclein in the pathophysiology of the
disease are unknown. Although other neuronal cell types exhibit α-synuclein positive aggregates, substantia
nigra dopamine neurons display a selective vulnerability to α-synuclein mediated neurodegeneration. In this
thesis work I have focused on the possible mechanisms underlying the vulnerability of dopamine producing
neurons against α-synuclein induced neurotoxicity. To study the molecular interactions playing role in
α-synuclein mediated dopaminergic neurodegeneration, we investigated putative mechanisms that has been
implicated in α-synuclein toxicity. Interaction of the α-synuclein protein with other molecules has been
suggested to enhance the aggregation. We studied the interaction between the full-length α-synculein protein
and truncated α-synuclein in the rat substantia nigra. When the two forms are co-expressed the truncated form
promotes full-length α-syn aggregation and enhance the pathology caused by the full-length protein. We next
investigated the specific role of dopamine handling machinery in Parkinson’s disease pathophysiology and
treatment related motor complications. To study the involvement of cytosolic DA and age related increase in
the reactive DA species on α-syn toxicity, we utilized a transgenic mouse model carrying a hypomorphic
VMAT2 mutation. The elevated cytosolic dopamine in these mice led to an increased vulnerability to
α-synuclein overexpression. To show that this vulnerability was indeed dopamine dependent, we generated
recombinant adeno-associated viral vectors to transfer short hairpin RNA sequences targeting the
rate-limiting enzyme, tyrosine hydroxylase. Reducing dopamine production using the shRNA approach in
these mice rescued the vulnerability against α-synuclein in the nigral dopamine neurons. Our results implicate
the critical role of dopamine handling in Parkinson’s disease pathophysiology, thus suggest that regulating
the specific pathways through which DA mediates its toxic effects can prevent the potential
neurodegeneration. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1599796
- author
- Ulusoy, Ayse LU
- supervisor
-
- Deniz Kirik LU
- Anders Björklund LU
- opponent
-
- Emson, Piers C, The Babraham Institute, Babraham, Cambridge, UK
- organization
- publishing date
- 2010
- type
- Thesis
- publication status
- published
- subject
- keywords
- Parkinson's disease, adeno-associated virus, dopamine, α-synuclein, tyrosine hydroxylase, RNAinterference, shRNA, substantia nigra, animal models, dyskinesia
- in
- Lund University Faculty of Medicine Doctoral Dissertation Series
- volume
- 2010:61
- pages
- 178 pages
- publisher
- Department of Experimental Medical Science, Lund Univeristy
- defense location
- Segerfalk Lecture Hall
- defense date
- 2010-05-22 09:15:00
- ISSN
- 1652-8220
- ISBN
- 978-91-86443-76-4
- language
- English
- LU publication?
- yes
- id
- 68b33d67-dac6-4c89-98a5-f68997360f5c (old id 1599796)
- date added to LUP
- 2016-04-01 15:04:39
- date last changed
- 2020-09-16 16:15:14
@phdthesis{68b33d67-dac6-4c89-98a5-f68997360f5c,
abstract = {{The pathological hallmark of Parkinson’s disease is dopaminergic neurodegeneration in the substantia nigra<br/><br>
pars compacta neurons and accumulation of α-synuclein containing aggregates in the surviving neurons. The<br/><br>
cause of cell death in Parkinson’s disease and the involvement of α-synuclein in the pathophysiology of the<br/><br>
disease are unknown. Although other neuronal cell types exhibit α-synuclein positive aggregates, substantia<br/><br>
nigra dopamine neurons display a selective vulnerability to α-synuclein mediated neurodegeneration. In this<br/><br>
thesis work I have focused on the possible mechanisms underlying the vulnerability of dopamine producing<br/><br>
neurons against α-synuclein induced neurotoxicity. To study the molecular interactions playing role in<br/><br>
α-synuclein mediated dopaminergic neurodegeneration, we investigated putative mechanisms that has been<br/><br>
implicated in α-synuclein toxicity. Interaction of the α-synuclein protein with other molecules has been<br/><br>
suggested to enhance the aggregation. We studied the interaction between the full-length α-synculein protein<br/><br>
and truncated α-synuclein in the rat substantia nigra. When the two forms are co-expressed the truncated form<br/><br>
promotes full-length α-syn aggregation and enhance the pathology caused by the full-length protein. We next<br/><br>
investigated the specific role of dopamine handling machinery in Parkinson’s disease pathophysiology and<br/><br>
treatment related motor complications. To study the involvement of cytosolic DA and age related increase in<br/><br>
the reactive DA species on α-syn toxicity, we utilized a transgenic mouse model carrying a hypomorphic<br/><br>
VMAT2 mutation. The elevated cytosolic dopamine in these mice led to an increased vulnerability to<br/><br>
α-synuclein overexpression. To show that this vulnerability was indeed dopamine dependent, we generated<br/><br>
recombinant adeno-associated viral vectors to transfer short hairpin RNA sequences targeting the<br/><br>
rate-limiting enzyme, tyrosine hydroxylase. Reducing dopamine production using the shRNA approach in<br/><br>
these mice rescued the vulnerability against α-synuclein in the nigral dopamine neurons. Our results implicate<br/><br>
the critical role of dopamine handling in Parkinson’s disease pathophysiology, thus suggest that regulating<br/><br>
the specific pathways through which DA mediates its toxic effects can prevent the potential<br/><br>
neurodegeneration.}},
author = {{Ulusoy, Ayse}},
isbn = {{978-91-86443-76-4}},
issn = {{1652-8220}},
keywords = {{Parkinson's disease; adeno-associated virus; dopamine; α-synuclein; tyrosine hydroxylase; RNAinterference; shRNA; substantia nigra; animal models; dyskinesia}},
language = {{eng}},
publisher = {{Department of Experimental Medical Science, Lund Univeristy}},
school = {{Lund University}},
series = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
title = {{Modeling pathophysiological aspects of Parkinson’s disease: Manipulating DA handling and alpha-synuclein expression in the nigrostriatal pathway using viral vectors}},
volume = {{2010:61}},
year = {{2010}},
}