Intracellular dynamics of Alzheimer disease-related proteins
Author: Selivanova, Alexandra
Date: 2007-06-15
Location: Konferensrummet NVS, Novum, plan 4, Huddinge
Time: 09.00
Department: Institutionen för neurobiologi, vårdvetenskap och samhälle / Department of Neurobiology, Care Sciences and Society
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thesis.pdf (373.8Kb)
Abstract
Alzheimer’s disease is a devastating neurodegenerative disorder
characterized by accumulation of amyloid-β peptide and formation of
amyloid plaques and aggregates of hyperphosphorylated tau protein forming
neurofibrillary tangles.
The amyloid-β peptide is generated through sequential processing of the
amyloid precursor protein (APP) by β- and γ-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-β 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.
List of papers:
I. Selivanova A, Winblad B, Farmery MR, Dantuma NP, Ankarcrona M (2006). "COPI-mediated retrograde transport is required for efficient gamma-secretase cleavage of the amyloid precursor protein." Biochem Biophys Res Commun 350(1): 220-6. Epub 2006 Sep 18
Pubmed
II. Selivanova A, Winblad B, Dantuma NP, Farmery MR (2007). "Biogenesis and processing of the amyloid precursor protein in the early secretory pathway." Biochem Biophys Res Commun 357(4): 1034-9. Epub 2007 Apr 19
Pubmed
III. Cunnea PM, Selivanova A, Bogdanovic N, Farmery MR, Spyrou G (2007). "ERdj5 interacts with amyloid precursor proteins and is expressed in Alzheimers disease." (Submitted)
IV. Verhoef LGGC, Selivanova A, Krutauz D, Glickman M, Dantuma NP (2007). "Proteasome substrates require a minimum length for efficient processing by proteasome-associated deubiquitylation activity and subsequent degradation." (Submitted)
I. Selivanova A, Winblad B, Farmery MR, Dantuma NP, Ankarcrona M (2006). "COPI-mediated retrograde transport is required for efficient gamma-secretase cleavage of the amyloid precursor protein." Biochem Biophys Res Commun 350(1): 220-6. Epub 2006 Sep 18
Pubmed
II. Selivanova A, Winblad B, Dantuma NP, Farmery MR (2007). "Biogenesis and processing of the amyloid precursor protein in the early secretory pathway." Biochem Biophys Res Commun 357(4): 1034-9. Epub 2007 Apr 19
Pubmed
III. Cunnea PM, Selivanova A, Bogdanovic N, Farmery MR, Spyrou G (2007). "ERdj5 interacts with amyloid precursor proteins and is expressed in Alzheimers disease." (Submitted)
IV. Verhoef LGGC, Selivanova A, Krutauz D, Glickman M, Dantuma NP (2007). "Proteasome substrates require a minimum length for efficient processing by proteasome-associated deubiquitylation activity and subsequent degradation." (Submitted)
Issue date: 2007-05-25
Rights:
Publication year: 2007
ISBN: 978-91-7357-234-7
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