Modeling and Mechanistic Investigation of α-synuclein aggregation

Alexander Svanbergsson

Research output: ThesisDoctoral Thesis (compilation)

31 Downloads (Pure)

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.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Experimental Medical Science
Supervisors/Advisors
  • Li, Jia-Yi, Supervisor
  • Snogerup-Linse, Sara, Assistant supervisor
  • Englund, Elisabet, Assistant supervisor
Award date2021 Dec 3
Place of PublicationLund
Publisher
Print ISBNs978-91-8021-143-7
Publication statusPublished - 2021

Bibliographical note

Defence details
Date: 2021-12-03
Time: 13:15
Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/s/64082215394
External reviewer(s)
Name: Luk, Kelvin C.
Title: Associate Professor
Affiliation: Perelman School of Medicine University of Pennsylvania

Subject classification (UKÄ)

  • Neurosciences
  • Cell and Molecular Biology

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