Eylem Seç
Aggregation and Conformation of Alpha-Synuclein: Effects of Ligand Binding and Phosphomimetics
Başlık:
Aggregation and Conformation of Alpha-Synuclein: Effects of Ligand Binding and Phosphomimetics
Yazar:
Paskins, Aimee Rebecca, author.
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (355 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-09C.
Advisors: David Smith.
Özet:
Parkinson's disease (PD) affects 1 in 500 of the UK population. A critical step in disease aetiology is the formation of Lewy bodies (LBs), deposits of aggregated alpha-synuclein (alphasyn) as amyloid inclusions, within surviving neurons. It is well established that alphasyn within LBs has undergone a variety of post-translational modifications, including S129 phosphorylation, and LBs are known to be rich in metals such as copper. It has however, yet to be established how phosphorylation of alphasyn and metal ions influence in the pathology of PD, and if the formation of LBs can be prevented by the use of small molecule inhibitors. Electrospray ionisation-ion mobility spectrometry- mass spectrometry (ESI-IMSMS) was used to investigate the conformational changes to compact states of alphasyn known to be linked to amyloid formation, for WT and two alphasyn mutants mimicking phosphorylation at S87 and S129, in the presence of copper, and their aggregation was monitored by thioflavin-T assays. Results demonstrate that the conformational state of alphasyn can be modulated by interactions with copper, causing an increase in the compact state, leading to an increased rate of aggregation. S129D alphasyn showed the highest affinity for copper, and the fastest aggregation rates overall. SH-SY5Y cell culture models were used to investigate intracellular aggregation and phosphorylation state upon copper exposure. Increased copper concentration correlated with increased formation of unmodified and phosphorylated intracellular aggregates, an increase in apoptosis, and decreased cell viability. ESI-IMS-MS demonstrated curcumin and its derivatives were able to disrupt amyloid assembly, via prevention of autofragmentation and dissociation of low-order oligomers, thus preventing the aggregation of alphasyn. In SH-SY5Y model used however, curcumins were unable to prevent the metal-induced intracellular aggregation of alphasyn. Together, results support the hypothesis that phosphorylation has a key role in PD progression, and demonstrated that modified curcumins may be a potential therapeutic for PD.
Notlar:
School code: 8818
Konu Başlığı:
Tüzel Kişi Ek Girişi:
Mevcut:*
Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(697092.1) | 697092-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
On Order
Liste seç
Bunu varsayılan liste yap.
Öğeler başarıyla eklendi
Öğeler eklenirken hata oldu. Lütfen tekrar deneyiniz.
:
Select An Item
Data usage warning: You will receive one text message for each title you selected.
Standard text messaging rates apply.