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Alpha-synuclein aggregation: visualization by X-ray techniques and its modulation by iron

Carboni, Eleonora
Doctoral thesis
Date of Examination: 2016-10-19
Date of issue: 2017-09-06
Advisor: Lingor, Paul Prof. Dr.
Referee: Salditt, Tim Prof. Dr.
Referee: Outeiro, Tiago Fleming Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0023-3EF2-D

 

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Abstract

English

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. It’s a progressive disease that can be treated only symptomatically and its causes are still not fully understood. Two main factors have shown to play a pivotal role in the etiopathology of PD: the metal dys-homeostasis and the presence of aggregated protein structures (Lewy Bodies) that are mainly composed of the protein alpha-synuclein (aSyn). The present work had the aim of better characterizing the role of the interaction between aSyn and iron (Fe) in PD. A combination of X-ray-based imaging techniques together with cell-biology methods and animal models was applied for studying this interactions. The analysis showed for the first time the presence of mostly extracellularly located highly ordered structures in brain tissue of PD patients using x-ray diffraction techniques. The distribution and quantification of the trace metals in the samples exhibited an increased Fe content in line with previous data on metal dys-homeostasis in PD. Particle-induced X-ray emission was able to prove that aSyn overexpression affects the metal content in primary midbrain neurons in presence and in absence of excessive Fe supply. Furthermore, overexpression of aSyn changed the expression of metal transport proteins. A murine model of aSyn aggregation (prnp.aSyn.A53T) in combination with mild Fe intoxication showed that this interaction leaded to the appearance of motor learning deficits. In this murine paradigm DFP, a Fe chelator that is able to cross the blood brain barrier, could rescue the deleterious effects of Fe intoxication. This suggested that Fe chelators could be combined with the symptomatic therapies for PD for future treatments as first clinical trials with this drug also indicate. This work used a combination of biological and X-ray imaging techniques to shed a light on the interaction of aSyn and Fe and thus contributed to a deeper understanding of PD pathomechanisms and future disease-modifying translational therapies.
Keywords: iron; X-ray; X-ray diffraction; X-ray fluorescence; alpha-synuclein; XRD; XRF; synuclein; deferiprone; mouse model; behavioral test; aggregation; Parkinson's disease; prnp.aSyn.A53T; A53T
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