Advanced

Modeling pathophysiological aspects of Parkinson’s disease: Manipulating DA handling and alpha-synuclein expression in the nigrostriatal pathway using viral vectors

Ulusoy, Ayse LU (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:
author
supervisor
opponent
  • Emson, Piers C, The Babraham Institute, Babraham, Cambridge, UK
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Parkinson's disease, adeno-associated virus, dopamine, α-synuclein, tyrosine hydroxylase, RNA interference, 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
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
2010-05-05 14:23:51
date last changed
2018-05-29 12:11:36
@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},
  keyword      = {Parkinson's disease,adeno-associated virus,dopamine,α-synuclein,tyrosine hydroxylase,RNA
interference,shRNA,substantia nigra,animal models,dyskinesia},
  language     = {eng},
  pages        = {178},
  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},
}