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Dissertation zugänglich unter
URN: urn:nbn:de:gbv:18-53297
URL: http://ediss.sub.uni-hamburg.de/volltexte/2011/5329/


Mechanism of neuronal death in familial encephalopathy with neuroserpin inclusion bodies (FENIB); Implications for mutant neuroserpin degradation – a study in mus musculus

Mechanismen der Neurodegeneration bei der familiären Enzephalopathie mit Neuroserpin Einschlüssen (FENIB); Implikationen für den Abbau mutierten Neuroserpins - eine Studie in mus musculus

Schipanski, Angela

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 Dokument 1.pdf (8.807 KB) 


Freie Schlagwörter (Deutsch): Demenz , Serpin , Proteastase , Unfolded Protein Response , Neurodegeneration
Freie Schlagwörter (Englisch): dementia , serpin, autophagy , unfolded protein response , proteostasis
Basisklassifikation: 42.13
Institut: Biologie
DDC-Sachgruppe: Biowissenschaften, Biologie
Dokumentart: Dissertation
Hauptberichter: Glatzel, Markus (Prof. Dr.)
Sprache: Englisch
Tag der mündlichen Prüfung: 23.06.2011
Erstellungsjahr: 2011
Publikationsdatum: 27.09.2011
Kurzfassung auf Englisch: The inheritable dementia FENIB (familial encephalopathy with neuroserpin inclusion bodies) is caused by the accumulation of ordered polymers of mutant neuroserpin within the endoplasmic reticulum (ER) of neurons. Intracellular deposits of mutant neuroserpin challenge the fidelity of protein homeostasis, also proteostasis, which ensures a balanced interplay between protein synthesis, folding and clearance. Maintenance of cytosolic neuronal proteostasis is supported by the ubiquitin proteasome system (UPS) and the autophagy-lysosomal pathways. As mutant neuroserpin accumulates in the ER of neurons, we addressed how disturbance of ER proteostasis leads to neurodegeneration in a murine model of FENIB.
Specifically, we studied the role of ER associated degradation (ERAD) and autophagy on mutant neuroserpin degradation in mice expressing mutant Tg(NSS49P) or wild-type Tg(NS) neuroserpin. We showed that mutant neuroserpin is specifically degraded by the proteasome via ERAD and non-specifically by autophagy. Only when the proteasomal activity is impaired, does autophagy contribute to mutant neuroserpin degradation. Further on, we studied the impact of the unfolded protein response (UPR) in regulating amounts of aggregated proteins. Transient induction of UPR in Tg(NSS49P) mice controls polymeric protein formation and aggregation in young mice. With increasing age, the capacity to mount UPR ceases and the amount of polymeric proteins and aggregates rises exponentially.
Thus, our data support the concept of disturbed neuronal proteostasis in dementias and point towards age-related exhaustion of proteostasis maintaining mechanisms which are decisive for disease progression in dementias with intracellular protein depositions.

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