Dissertation Inga Petersen (Dep. Of Pharmacy)

Neurodegenerative diseases are currently the fastest growing cause of death globally. Among these, Parkinson's disease is the second most common, with over 6 million affected. Central to the progression of Parkinson's disease and related pathologies is the aggregation of protein alpha-synuclein (αSyn) into oligomers and fibrils that, when spread between neurons, cause neurodegeneration.

The need for a treatment to prevent αSyn aggregation – and potentially halt disease progression – is urgent. In her PhD project, Inga Petersen has designed two new antibodies showing up to 20-fold increased binding strength to αSyn aggregates than previously possible, also binding to the very smallest aggregates, which are assumed to be the most toxic. Petersen has also developed αSyn mutants in order to produce αSyn oligomers with high stability already in its early phases, which can facilitate studies of mechanisms in the early stages of Parkinson's disease

Inga Petersen has also designed an antibody that in in vitro studies shows decidedly improved abilities to cross the blood-brain barrier, in turn enabling more efficient transport of potential drugs to the brain.

In summary, Petersen's thesis shows that increasing the valency of an antibody is a possible strategy to enhance its binding strength to αSyn aggregates. However, to effectively target pathologically relevant αSyn species, a more selective targeting approach may be required, possibly through a conformational epitope exclusive to αSyn oligomers.

Opponent

Daniel Otzen, Professor of Nanobiotechnology, Aarhus University (DK)

Supervisors

Greta Hultqvist, Associate Professor, Uppsala University
Dag Sehlin, Associate Professor, Uppsala University
Anna Erlandsson, Associate Professor, Uppsala University

Researcher Bio

Inga Petersen obtained her bachelor's degree in Biology at the University of Rostock followed by a Master's degree in Molecular Biology and Physiology at the University of Greifswald. After a research internship and a position as a research assistant at Uppsala University, Inga was recruited to Greta Hultqvist's research group in Protein drug design where she began her PhD studies.

Read thesis

Targeting pathological alpha-synuclein: Protein engineering towards improved antibody-based therapeutics and their delivery to the brain (Acta Universitatis Upsaliensis, 2024)