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

Författare:
  • Ayse Ulusoy
Publiceringsår: 2010
Språk: Engelska
Sidor:
Publikation/Tidskrift/Serie: Lund University, Faculty of Medicine Doctoral Dissertation Series
Volym: 2010:61
Dokumenttyp: Doktorsavhandling
Förlag: Department of Experimental Medical Science, Lund Univeristy

Sammanfattning

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.

Disputation

2010-05-22
09:15
Segerfalk Lecture Hall
  • Piers C Emson

Nyckelord

  • Neurosciences
  • Parkinson's disease
  • adeno-associated virus
  • dopamine
  • α-synuclein
  • tyrosine hydroxylase
  • RNAinterference
  • shRNA
  • substantia nigra
  • animal models
  • dyskinesia

Övriga

Published
  • Brain Repair and Imaging in Neural Systems (BRAINS)
  • Deniz Kirik
  • Anders Björklund
  • ISSN: 1652-8220
  • ISBN: 978-91-86443-76-4

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