Intracellular dynamics of Alzheimer disease-related proteins
Sammanfattning: Alzheimer’s disease is a devastating neurodegenerative disorder characterized by accumulation of amyloid-? peptide and formation of amyloid plaques and aggregates of hyperphosphorylated tau protein forming neurofibrillary tangles. The amyloid-? peptide is generated through sequential processing of the amyloid precursor protein (APP) by ?- and ?-secretase. This processing is thought to occur at different locations along the intracellular secretory pathway that APP has to travel prior to reaching the cell surface. In our studies we have focused on the role of secretory pathway trafficking of APP in its amyloidogenic processing. In particular, we have investigated the significance of retrograde protein transport mediated by coatomer protein 1 in processing of APP. The potential significance of a novel endoplasmic reticulum (ER) chaperone ERdj5, belonging to a group of proteins that help the cell to handle misfolded proteins, in amyloidogenic processing of APP and AD pathogenesis was studied. We have also explored the mechanisms underlying the accumulation of an aberrant form of ubiquitin (that normally serves as a proteasomal degradation signal for intracellular and misfolded proteins) UBB+1 in neurodegenerative disorders, including AD, and its inhibitory effect on proteasomal function. Studies included in this thesis demonstrate that (i) retrograde transport of proteins between Golgi complex and the endoplasmic reticulum mediated by COPI is required for proper intracellular trafficking of APP and its amyoidogenic processing, (ii) early steps in the secretory pathway occurring in the ER and Golgi are significant for amyloidogenic processing of APP, (iii) ERdj5 binds to immature APP, enhances its processing to amyloid-? peptide, and has altered expression in AD brain, (iv) stability of UBB+1 and its accumulation in cells in AD is due to the shortness of its C-terminal extension, leading us to propose that proteasomal substrates need a certain length in order to efficiently degraded by the proteasome. The major premise of this thesis was to follow the turnover of proteins in the cell: from synthesis and quality control in the endoplasmic reticulum, trafficking along the secretory pathway to a protein’s site of action and finally protein degradation by the proteasome. We have demonstrated that all these pathways are significant for neurodegenerative disorders, such as Alzheimer’s disease.
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