Characterization and therapeutic targeting of Parkinson’s-related LRRK2

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More than a decade ago, and during the attempts to understand Parkinson’s disease (PD), scientists identified Leucine-Rich Repeat Kinase 2 (LRRK2) as a protein related to PD development. Since then, different research groups have focused on developing tools to investigate and target LRRK2 function and activity. LRRK2 is a uniquely large protein, that becomes active upon dimerization, i.e. when two units of the protein come together. Although a number of LRRK2 inhibitors has been developed over the past few years, these inhibitors result in side effects that were observed during animal and preclinical studies. Thus, different strategies to regulate the activity of LRRK2 are needed.
In the work presented in this thesis, we provided an alternative approach by targeting the LRRK2 dimerization process. We designed, tested, and proved that small peptides can be used to occupy the site at which the two units of LRRK2 stick together. In this way, we prevented the formation of the active dimer form of LRRK2 and reduced its activity. Importantly, this approach didn’t result in the same side-effects of classical inhibitors upon testing in human cells.
In order to better understand the function of LRRK2, we also identified nanobodies (small protein that can specifically bind to a target of interest) that can bind LRRK2 and regulate its activity. These nanobodies will help identifying the exact structure of LRRK2 and developing of new therapeutics.
Originele taal-2English
KwalificatieDoctor of Philosophy
Toekennende instantie
  • Rijksuniversiteit Groningen
Begeleider(s)/adviseur
  • van Haastert, Peter, Supervisor
  • Kortholt, Arjan, Supervisor
Datum van toekenning28-mrt-2022
Plaats van publicatie[Groningen]
Uitgever
DOI's
StatusPublished - 2022

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