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| Investigation of the role of collapsin response mediator 4 in Huntington's disease Nicoletti, Cecilia |
| Haupttitel | Investigation of the role of collapsin response mediator 4 in Huntington's disease |
| Titelvariante | Untersuchung der Rolle von Collapsin Response Mediator 4 in Chorea Huntington |
| Autor | Nicoletti, Cecilia
Geburtsort: Florenz, Italien |
| Gutachter | Prof. Dr. med. J. Priller |
| weitere Gutachter | Prof. Dr. med. F. Heppner Priv.-Doz. Dr. C. Saft |
| Freie Schlagwörter | Huntington's Disease; mhtt; inclusions; CRMP4; cytoskeleton |
| DDC | 610 Medizin und Gesundheit |
| Zusammenfassung | Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by the ac- cumulation in the affected neuronal population of N-terminal huntingtin (htt) fragments bear- ing elongated polyglutamine (polyQ) tracts. Several lines of evidence indicate that the process of htt misfolding and aggregation is associated with cytotoxicity in HD models and patients. Thus, the identification and characterization of proteins that can modulate this process is criti- cal for understanding HD pathogenesis and therapy development. Here, we report a depletion of collapsin response mediator protein 4 (CRMP4) protein levels in a cell culture model of HD. CRMP4 belongs to the collapsin response mediator protein family that mediates many aspects of neuronal development and plasticity by regulating cytoskeleton dynamics. Cell-free and cell-based assays demonstrate that CRMP4 reduces polyQ-mediated htt ag- gregation and toxicity. Furthermore our results show that this effect may be linked to a re- arrangement of Actin cytoskeleton. Indeed both, CRMP4 and filamentous Actin (F-Actin), are recruited into the intracellular inclusions formed by mutant huntingtin (mhtt), while over- expression of CRMP4 partially detached F-Actin from the mhtt aggregates. CRMP4 is cleaved by Calpain-1 when mhtt is expressed. This result links to previous findings showing the same proteolytic cleavage of CRMP4 when cells were subject to excitotoxicity. The proteolysis of CRMP4 may therefore be a marker of neuronal toxicity. This work suggests a functional link between mhtt and CRMP4 and a role for CRMP4 as a new modulator of mhtt. Further stud- ies are important for understanding whether CRMP4 can help deciphering the early cellular pathomechanisms in HD. |
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| Fachbereich/Einrichtung | Medizinische Fakultät Charité - Universitätsmedizin Berlin |
| Erscheinungsjahr | 2011 |
| Dokumententyp/-Sammlungen | Dissertation |
| Medientyp/Format | Text |
| Sprache | Englisch |
| Rechte | Nutzungsbedingungen |
| Tag der Disputation | 09.09.2011 |
| Erstellt am | 12.08.2011 - 08:19:02 |
| Letzte Änderung | 06.09.2011 - 07:54:15 |
| Statische URL | http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000023755 |
| URN | urn:nbn:de:kobv:188-fudissthesis000000023755-1 |
| Zugriffsstatistik | |
| E-Mail-Adresse | cecilia_nicol@hotmail.com |
