Characterization of α-synuclein oligomers: Implications for Lewy Body Disorders

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Näsström, ThomasUppsala universitet,Institutionen för folkhälso- och vårdvetenskap,Lannfelt (författare)

Characterization of α-synuclein oligomers : Implications for Lewy Body Disorders

BokEngelska2011

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Uppsala :Acta Universitatis Upsaliensis,2011
70 s.
electronicrdacarrier

Nummerbeteckningar

LIBRIS-ID:oai:DiVA.org:uu-160102
ISBN:9789155481988
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-160102URI

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Språk:engelska
Sammanfattning på:engelska

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Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,1651-6206 ;717

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Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy are disorders featuring accumulation of Lewy bodies in brain. The main component of these large insoluble intracellular inclusions is the presynaptic protein alpha-synuclein (α-synuclein). It is generally believed that α-synuclein monomers adopt an abnormal conformation that favors the formation of soluble oligomers or protofibrils and, eventually, insoluble fibrils depositing as Lewy bodies. Notably, the intermediately sized oligomers/protofibrils seem to have particular neurotoxic effects. Several factors may influence the formation of α-synuclein oligomers/protofibrils, e.g. the reactive aldehydes 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) formed during oxidative stress. The overall aims of this thesis were to investigate biophysical and biochemical properties of in vitro generated α-synuclein oligomers, characterize their functional effects on cell and animal disease models as well as to explore whether their formation could be prevented in a cell culture model for oligomerization. Here, it was found that α-synuclein rapidly formed oligomers after incubation with both ONE and HNE. The resulting oligomers were stable and did not continue to form insoluble fibrils. By comparing HNE- and ONE induced α-synuclein oligomers biochemically they were both found to exhibit extensive β-beta sheet structure and had a molecular size of ~2000 kDa. However, they differed in morphology; the ONE induced α-synuclein oligomers described round amorphous species whereas the HNE induced α-synuclein oligomers appeared as elongated protofibril-like structures. Both these oligomers were cell internalized to varying degrees and induced toxicity in neuroblastoma cells. In addition, the ONE induced α-synuclein oligomers seemed to initiate aggregation of monomeric α-synuclein in vitro, but failed to do so in vivo. Finally, treatment of α-synuclein overexpressing cells with monoclonal antibodies specific for α-synuclein significantly reduced aggregation and lowered levels of the protein, suggesting increased turnover in these cells. To conclude, this thesis has characterized different oligomeric α-synuclein species, which may have properties similar to soluble species central to the pathogenesis of Parkinson’s disease and other disorders with α-synuclein pathology. For therapeutic strategies it is important to selectively target such harmful protein species and avoid interaction with other forms of α-synuclein, which may have vital physiological cellular functions.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Geriatrik hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Geriatrics hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine hsv//eng
Parkinson’s disease; Alpha-synuclein; Lewy bodies; Oligomers; Reactive aldehydes; monoclonal antibody
Medical Science
Medicinsk vetenskap

Biuppslag (personer, institutioner, konferenser, titlar ...)

Ingelsson, Martin,MD, PhDUppsala universitet,Institutionen för folkhälso- och vårdvetenskap (preses)
Bergström, Joakim,PhDUppsala universitet,Institutionen för folkhälso- och vårdvetenskap (preses)
Lannfelt, Lars,MD, PhDUppsala universitet,Institutionen för folkhälso- och vårdvetenskap (preses)
Jensen, Poul Henning,MD, PhDInstitute of Medical Biochemistry, University of Aarhus, Aarhus, Denmark (opponent)
Uppsala universitetInstitutionen för folkhälso- och vårdvetenskap (creator_code:org_t)

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