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AuthorCaesar, Mareikedc.contributor.author
Date of accession2016-04-26T10:03:56Zdc.date.accessioned
Available in OPARU since2016-04-26T10:03:56Zdc.date.available
Year of creation2015dc.date.created
AbstractParkinson’s disease (PD) is, after Alzheimer’s disease, the most common neurodegenerative disorder. Mutations in the leucine rich repeat kinase 2 (LRRK2) are the most common known cause of familial PD but also constitute about 3.5 % of all sporadic PD cases. This work focuses on the effects of LRRK2 mutations on cytoskeletal function and on the innate immune system. Findings from animal models were translated to human material to assess their relevance in human disease states. Changes in actin and tubulin dynamics and structure that were shown by biochemical and histochemical methods. These changes are likely to be the root cause for the functional alterations observed in the migratory behavior of mouse and human fibroblasts carrying LRRK2 mutations. Similar alterations in actin dynamics were found in the synaptic compartment of transgenic mice. Hence, unlike other studies which focus on PD-linked alterations in the actin cytoskeleton I was able to replicate these changes in several distinct postnatal systems and in patient derived material. Concerning alterations in the innate immune system I describe a global mutation-dependent decrease in extracellular progranulin which is seen in a whole range of cell types including mouse and human fibroblasts and murine immune cells. The relevance to the CNS becomes apparent by the decrease in extracellular progranulin in cultures of mutant microglia and the decrease in progranulin in the CSF of presymptomatic mice. However, CSF progranulin levels show a significant increase when motor symptoms start to appear. Further research is required to establish whether reversion of these alterations will ameliorate functional defects.dc.description.abstract
Languagededc.language.iso
PublisherUniversität Ulmdc.publisher
LicenseStandarddc.rights
Link to license texthttps://oparu.uni-ulm.de/xmlui/license_v3dc.rights.uri
KeywordLRRK2dc.subject
KeywordProgranulindc.subject
Dewey Decimal GroupDDC 610 / Medicine & healthdc.subject.ddc
MeSHCytoskeletondc.subject.mesh
MeSHInflammationdc.subject.mesh
MeSHLRRK2 protein, humandc.subject.mesh
MeSHLRRK2 protein, mousedc.subject.mesh
MeSHMicrogliadc.subject.mesh
MeSHParkinson diseasedc.subject.mesh
TitleCellular and systemic effects of Parkinson’s disease-related LRRK2 mutations: An investigation of cytoskeletal function and the innate immune system in transgenic mice and human LRRK2 mutation carriersdc.title
Resource typeDissertationdc.type
DOIhttp://dx.doi.org/10.18725/OPARU-3955dc.identifier.doi
PPN858774704dc.identifier.ppn
URNhttp://nbn-resolving.de/urn:nbn:de:bsz:289-vts-100036dc.identifier.urn
GNDEntzündungdc.subject.gnd
GNDParkinson-Krankheitdc.subject.gnd
GNDZellskelettdc.subject.gnd
FacultyMedizinische Fakultätuulm.affiliationGeneral
Date of activation2016-04-25T09:12:53Zuulm.freischaltungVTS
Peer reviewneinuulm.peerReview
Shelfmark print versionW: W-H 14.674uulm.shelfmark
DCMI TypeTextuulm.typeDCMI
VTS-ID10003uulm.vtsID
CategoryPublikationenuulm.category
University Bibliographyjauulm.unibibliographie


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