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Aggresome formation by mutant prion proteins: the unfolding role of proteasomes in familial prion disorders.
- Source :
-
Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2003 Feb; Vol. 5 (1), pp. 15-23. - Publication Year :
- 2003
-
Abstract
- Although familial prion disorders are a direct consequence of mutations in the prion protein gene, the underlying mechanisms leading to neurodegeneration remain unclear. Potential pathogenic mechanisms include abnormal cellular metabolism of the mutant prion protein (PrP(M)), or destabilization of PrP(M) structure inducing a change in its conformation to the pathogenic PrP-scrapie (PrP(Sc)) form. To further clarify these mechanisms, we investigated the biogenesis of mutant PrP V203I and E211Q associated with Creutzfeldt-Jakob disease, and PrP Q212P associated with Gerstmann-Straussler-Scheinker syndrome in neuroblastoma cells. We report that all three PrP(M) forms accumulate similarly in the cytosol in response to proteasomal inhibition, and finally assemble as classical aggresomes. Since the three PrP(M) forms tested in this report are distinct, we propose that sequestration of misfolded PrP(M) into aggresomes is likely a general response of the cellular quality control that is not specific to a particular mutation in PrP. Moreover, since PrP has the remarkable ability to refold into PrP(Sc) that can subsequently replicate, PrP(M) sequestered in aggresomes may cause neurotoxicity by both direct and indirect pathways; directly through PrP(Sc) aggregates, and indirectly by depleting normal PrP, through induction of a cellular stress response, or by other undefined pathways. On the other hand, sequestered PrP(M) may be relatively inert, and cellular toxicity may be mediated by early intermediates in aggresome formation. Taken together, these observations demonstrate the role of proteasomes in the pathogenesis of familial prion disorders, and argue for further explanation of its mechanistic details.
- Subjects :
- Antibodies, Anti-Idiotypic immunology
Blotting, Western
Brain metabolism
Brain pathology
Cell Aggregation genetics
Cell Culture Techniques
Creutzfeldt-Jakob Syndrome genetics
Fluorescent Antibody Technique
Gene Expression genetics
Gerstmann-Straussler-Scheinker Disease genetics
Green Fluorescent Proteins
Humans
Luminescent Proteins genetics
Neuroblastoma genetics
Neuroblastoma metabolism
Neuroblastoma pathology
Prion Diseases immunology
Prions immunology
Proteasome Endopeptidase Complex
Transfection methods
Cysteine Endopeptidases genetics
Cysteine Endopeptidases metabolism
Multienzyme Complexes genetics
Multienzyme Complexes metabolism
Point Mutation genetics
Prion Diseases genetics
Prion Diseases metabolism
Prions genetics
Prions metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1387-2877
- Volume :
- 5
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of Alzheimer's disease : JAD
- Publication Type :
- Academic Journal
- Accession number :
- 12590162
- Full Text :
- https://doi.org/10.3233/jad-2003-5103