Modeling and Mechanistic Investigation of α-synuclein aggregation
Svanbergsson, Alexander LU
(2021)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Our understanding of the α-synuclein aggregation process and the consequences thereof is currently limited, which in turn prevents the development of targeted therapeutic interventions. The work presented here, as a part of this thesis, is focused on expanding our understanding of the molecular events involved in α-synuclein aggregation. Towards this goal we have studied the impact of pathologically relevant forms of α-synuclein, namely A53T mutant α-synuclein and fibrillar α-synuclein, and characterized their impact on N-methyl-D-aspartate receptor (NMDAR) diffusion and function. We found both mutant and fibrillar α-synuclein, decreased the NMDAR diffusion and expression at the post-synapse. Moving further towards the mechanistic... (More)
- Our understanding of the α-synuclein aggregation process and the consequences thereof is currently limited, which in turn prevents the development of targeted therapeutic interventions. The work presented here, as a part of this thesis, is focused on expanding our understanding of the molecular events involved in α-synuclein aggregation. Towards this goal we have studied the impact of pathologically relevant forms of α-synuclein, namely A53T mutant α-synuclein and fibrillar α-synuclein, and characterized their impact on N-methyl-D-aspartate receptor (NMDAR) diffusion and function. We found both mutant and fibrillar α-synuclein, decreased the NMDAR diffusion and expression at the post-synapse. Moving further towards the mechanistic investigations we investigated the effect of two neuroprotective compounds on α-synuclein aggregation and found both compounds capable of clearing α-synuclein in cell and animal models potentially through autophagy related functions. In our efforts to scale mechanistic investigations we developed a high-throughput screening (HTS) capable FRET-based reporter for detection of α-synuclein aggregation in cells. Using this model, we performed a proof-of-concept screen of kinase inhibitors from which we identified three inhibitors with potent protective effects on α-synuclein aggregation. We further showed through mechanistic investigation that the protective effects likely involved lysosomal changes. Finally, in an effort to advance our knowledge of α-synuclein aggregation, we performed a genome-wide knockout screen to identify genes in the human genome with an impact on α-synuclein aggregation. This study also highlighted among other pathways the importance of the endolysosomal system in relation to α-synuclein aggregation. Many questions remain in regard to the molecular mechanisms involved in α-synuclein aggregation, but we hope our insights and models presented here will assist in the elucidation of the underlying mechanisms of α-synuclein aggregation. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/cfaf28f7-c763-4223-9483-75daaeec1ad9
- author
- Svanbergsson, Alexander
LU
- supervisor
-
- Jia-Yi Li LU
- Sara Snogerup-Linse LU
- Elisabet Englund LU
- opponent
-
- Associate Professor Luk, Kelvin C., Perelman School of Medicine University of Pennsylvania
- organization
- publishing date
- 2021
- type
- Thesis
- publication status
- published
- subject
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2021:136
- pages
- 81 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/s/64082215394
- defense date
- 2021-12-03 13:15:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-143-7
- language
- English
- LU publication?
- yes
- id
- cfaf28f7-c763-4223-9483-75daaeec1ad9
- date added to LUP
- 2021-11-12 15:29:08
- date last changed
- 2021-11-18 11:08:48
@phdthesis{cfaf28f7-c763-4223-9483-75daaeec1ad9,
abstract = {{Our understanding of the α-synuclein aggregation process and the consequences thereof is currently limited, which in turn prevents the development of targeted therapeutic interventions. The work presented here, as a part of this thesis, is focused on expanding our understanding of the molecular events involved in α-synuclein aggregation. Towards this goal we have studied the impact of pathologically relevant forms of α-synuclein, namely A53T mutant α-synuclein and fibrillar α-synuclein, and characterized their impact on N-methyl-D-aspartate receptor (NMDAR) diffusion and function. We found both mutant and fibrillar α-synuclein, decreased the NMDAR diffusion and expression at the post-synapse. Moving further towards the mechanistic investigations we investigated the effect of two neuroprotective compounds on α-synuclein aggregation and found both compounds capable of clearing α-synuclein in cell and animal models potentially through autophagy related functions. In our efforts to scale mechanistic investigations we developed a high-throughput screening (HTS) capable FRET-based reporter for detection of α-synuclein aggregation in cells. Using this model, we performed a proof-of-concept screen of kinase inhibitors from which we identified three inhibitors with potent protective effects on α-synuclein aggregation. We further showed through mechanistic investigation that the protective effects likely involved lysosomal changes. Finally, in an effort to advance our knowledge of α-synuclein aggregation, we performed a genome-wide knockout screen to identify genes in the human genome with an impact on α-synuclein aggregation. This study also highlighted among other pathways the importance of the endolysosomal system in relation to α-synuclein aggregation. Many questions remain in regard to the molecular mechanisms involved in α-synuclein aggregation, but we hope our insights and models presented here will assist in the elucidation of the underlying mechanisms of α-synuclein aggregation.}},
author = {{Svanbergsson, Alexander}},
isbn = {{978-91-8021-143-7}},
issn = {{1652-8220}},
language = {{eng}},
number = {{2021:136}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Modeling and Mechanistic Investigation of α-synuclein aggregation}},
url = {{https://lup.lub.lu.se/search/files/109638168/Alexander_Svanbergsson_web.pdf}},
year = {{2021}},
}