Immunogenetics of Parkinson's disease: Translational studies from rodents to humans
(2019) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2019(71).- Abstract
- Parkinson's disease (PD) is a complex neurodegenerative disease, characterized by a progressive loss
of dopaminergic neurons (DN) in the substantia nigra (SN) that innervate the striatum (ST) and pathological
accumulation of alpha-synuclein (αsyn) protein in aggregates called Lewy bodies (LB) and Lewy neurites
(LN). As a complex disease, PD presents a genetically heterogeneous origin. Mutations in single genes
account for 5-10% of all the cases. The remaining 90-95% of the cases present a complex and
multifactorial etiology, where there is an interplay between genetic and environmental factors that can
synergize to initiate the selective degeneration of DN in the SN and the development of PD pathology. In
this... (More) - Parkinson's disease (PD) is a complex neurodegenerative disease, characterized by a progressive loss
of dopaminergic neurons (DN) in the substantia nigra (SN) that innervate the striatum (ST) and pathological
accumulation of alpha-synuclein (αsyn) protein in aggregates called Lewy bodies (LB) and Lewy neurites
(LN). As a complex disease, PD presents a genetically heterogeneous origin. Mutations in single genes
account for 5-10% of all the cases. The remaining 90-95% of the cases present a complex and
multifactorial etiology, where there is an interplay between genetic and environmental factors that can
synergize to initiate the selective degeneration of DN in the SN and the development of PD pathology. In
this thesis, we aimed to contribute to the understating of the genetic architecture of PD, and its implications
in the DN loss and inflammatory aspects of the disease. We first explored differences in dopaminergic
susceptibility in two mouse strains that have a partial loss of Engrailed 1 (en1), a gene important for
dopaminergic neuronal development and survival. Using linkage analysis, we identified 23 loci determining
dopaminergic susceptibility. The next part of the thesis was focus on immune mechanisms in PD, for that
we used a congenic rat strain to study whether allelic variants of Mhc2ta, could affect α-syn-induced
pathology and dopaminergic neurodegeneration. Our results identified Mhc2ta as a facilitator and
aggravator of PD-like αsyn pathology. The last part of this thesis, was focused on determining the
frequency of known pathogenic variants causing PD, in a Swedish multi-center sample collection. Out of
7 studied pathogenic variants, we identified the LRRK2 p.G2019S mutation and SNCA duplication to be
present at a low frequency among Swedish patients, supporting the notion of the very complex genetic
architecture of PD, and suggesting other factors underlying PD risk in this population. Overall, the results
gathered in this thesis have given insight into the complex genetics underlying disease risk and identifying
MHC2TA as a potential modulator of the immune response in PD. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/5bd7277c-e2a1-4446-89df-78e57643bc9a
- author
- Jimenez, Itzia LU
- supervisor
-
- Maria Swanberg LU
- Jia-Yi Li LU
- opponent
-
- Dr. Tansey, Malú, Center for Translational Research in Neurodegenerative Disease, Institute for Neurological Diseases University of Florida
- organization
- publishing date
- 2019
- type
- Thesis
- publication status
- published
- subject
- keywords
- genetics; inflammation, α-synuclein, dopaminergic neurons, MHCII, Mhc2ta, Vra4, PFFs, microglia
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- volume
- 2019
- issue
- 71
- pages
- 113 pages
- publisher
- Lund University: Faculty of Medicine
- defense location
- Segerfalksalen, Wallenberg Neurocentrum
- defense date
- 2019-09-06 13:15:00
- ISSN
- 1652-8220
- ISBN
- 978-91-7619-800-1
- language
- English
- LU publication?
- yes
- id
- 5bd7277c-e2a1-4446-89df-78e57643bc9a
- date added to LUP
- 2019-08-20 11:31:34
- date last changed
- 2021-04-15 15:11:05
@phdthesis{5bd7277c-e2a1-4446-89df-78e57643bc9a, abstract = {{Parkinson's disease (PD) is a complex neurodegenerative disease, characterized by a progressive loss<br/>of dopaminergic neurons (DN) in the substantia nigra (SN) that innervate the striatum (ST) and pathological<br/>accumulation of alpha-synuclein (αsyn) protein in aggregates called Lewy bodies (LB) and Lewy neurites<br/>(LN). As a complex disease, PD presents a genetically heterogeneous origin. Mutations in single genes<br/>account for 5-10% of all the cases. The remaining 90-95% of the cases present a complex and<br/>multifactorial etiology, where there is an interplay between genetic and environmental factors that can<br/>synergize to initiate the selective degeneration of DN in the SN and the development of PD pathology. In<br/>this thesis, we aimed to contribute to the understating of the genetic architecture of PD, and its implications<br/>in the DN loss and inflammatory aspects of the disease. We first explored differences in dopaminergic<br/>susceptibility in two mouse strains that have a partial loss of Engrailed 1 (en1), a gene important for<br/>dopaminergic neuronal development and survival. Using linkage analysis, we identified 23 loci determining<br/>dopaminergic susceptibility. The next part of the thesis was focus on immune mechanisms in PD, for that<br/>we used a congenic rat strain to study whether allelic variants of Mhc2ta, could affect α-syn-induced<br/>pathology and dopaminergic neurodegeneration. Our results identified Mhc2ta as a facilitator and<br/>aggravator of PD-like αsyn pathology. The last part of this thesis, was focused on determining the<br/>frequency of known pathogenic variants causing PD, in a Swedish multi-center sample collection. Out of<br/>7 studied pathogenic variants, we identified the LRRK2 p.G2019S mutation and SNCA duplication to be<br/>present at a low frequency among Swedish patients, supporting the notion of the very complex genetic<br/>architecture of PD, and suggesting other factors underlying PD risk in this population. Overall, the results<br/>gathered in this thesis have given insight into the complex genetics underlying disease risk and identifying<br/>MHC2TA as a potential modulator of the immune response in PD.}}, author = {{Jimenez, Itzia}}, isbn = {{978-91-7619-800-1}}, issn = {{1652-8220}}, keywords = {{genetics; inflammation, α-synuclein, dopaminergic neurons, MHCII, Mhc2ta, Vra4, PFFs, microglia}}, language = {{eng}}, number = {{71}}, publisher = {{Lund University: Faculty of Medicine}}, school = {{Lund University}}, series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}}, title = {{Immunogenetics of Parkinson's disease: Translational studies from rodents to humans}}, url = {{https://lup.lub.lu.se/search/files/68626387/Itzia_Jimenez_web.pdf}}, volume = {{2019}}, year = {{2019}}, }