Intracellular Dynamics of Alzheimer Disease-related Proteins
Year: 2007
Type: dissertation
Abstract: Alzheimer’s disease is a devastating neurodegenerative disorder\ncharacterized by accumulation of amyloid-β peptide and formation of\namyloid plaques and aggregates of hyperphosphorylated tau protein forming\nneurofibrillary tangles.\n\nThe amyloid-β peptide is generated through sequential processing of the\namyloid precursor protein (APP) by β- and γ-secretase. This processing is\nthought to occur at different locations along the intracellular secretory\npathway that APP has to travel prior to reaching the cell surface.\n\nIn our studies we have focused on the role of secretory pathway\ntrafficking of APP in its amyloidogenic processing. In particular, we\nhave investigated the significance of retrograde protein transport\nmediated by coatomer protein 1 in processing of APP. The potential\nsignificance of a novel endoplasmic reticulum (ER) chaperone ERdj5,\nbelonging to a group of proteins that help the cell to handle misfolded\nproteins, in amyloidogenic processing of APP and AD pathogenesis was\nstudied. We have also explored the mechanisms underlying the accumulation\nof an aberrant form of ubiquitin (that normally serves as a proteasomal\ndegradation signal for intracellular and misfolded proteins) UBB+1 in\nneurodegenerative disorders, including AD, and its inhibitory effect on\nproteasomal function.\n\nStudies included in this thesis demonstrate that (i) retrograde transport\nof proteins between Golgi complex and the endoplasmic reticulum mediated\nby COPI is required for proper intracellular trafficking of APP and its\namyoidogenic processing, (ii) early steps in the secretory pathway\noccurring in the ER and Golgi are significant for amyloidogenic\nprocessing of APP, (iii) ERdj5 binds to immature APP, enhances its\nprocessing to amyloid-β peptide, and has altered expression in AD brain,\n(iv) stability of UBB+1 and its accumulation in cells in AD is due to the\nshortness of its C-terminal extension, leading us to propose that\nproteasomal substrates need a certain length in order to efficiently\ndegraded by the proteasome.\n\nThe major premise of this thesis was to follow the turnover of proteins\nin the cell: from synthesis and quality control in the endoplasmic\nreticulum, trafficking along the secretory pathway to a protein’s site of\naction and finally protein degradation by the proteasome. We have\ndemonstrated that all these pathways are significant for\nneurodegenerative disorders, such as Alzheimer’s disease.
Source: Figshare
Author: Alexandra Selivanova
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2157388057