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

Carboni, Eleonora

dc.contributor.advisor	Lingor, Paul Prof. Dr.
dc.contributor.author	Carboni, Eleonora
dc.date.accessioned	2017-09-06T10:43:13Z
dc.date.available	2017-09-06T10:43:13Z
dc.date.issued	2017-09-06
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-0023-3EF2-D
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-6449
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-6449
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc	570	de
dc.title	Alpha-synuclein aggregation: visualization by X-ray techniques and its modulation by iron	de
dc.type	doctoralThesis	de
dc.contributor.referee	Salditt, Tim Prof. Dr.
dc.date.examination	2016-10-19
dc.description.abstracteng	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.	de
dc.contributor.coReferee	Outeiro, Tiago Fleming Prof. Dr.
dc.subject.eng	iron	de
dc.subject.eng	X-ray	de
dc.subject.eng	X-ray diffraction	de
dc.subject.eng	X-ray fluorescence	de
dc.subject.eng	alpha-synuclein	de
dc.subject.eng	XRD	de
dc.subject.eng	XRF	de
dc.subject.eng	synuclein	de
dc.subject.eng	deferiprone	de
dc.subject.eng	mouse model	de
dc.subject.eng	behavioral test	de
dc.subject.eng	aggregation	de
dc.subject.eng	Parkinson's disease	de
dc.subject.eng	prnp.aSyn.A53T	de
dc.subject.eng	A53T	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-0023-3EF2-D-5
dc.affiliation.institute	Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)	de
dc.subject.gokfull	Biologie (PPN619462639)	de
dc.identifier.ppn	1006090991 1000140059

Files in this item

Name:CarboniEleonora_Dissertation.pdf

Size:4.039Mb

Format:PDF

View/Open

Name:: CarboniEleonora_Dissertation.pdf
Size:: 4.039Mb
Format:: PDF

View/Open

This item appears in the following Collection(s)

GGNB - Göttinger Graduiertenzentrum für Neurowissenschaften, Biophysik und molekulare Biowissenschaften [1114]
GGNB - Göttingen Graduate Center for Neurosciences, Biophysics and Molecular Biosciences

Show simple item record