QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, August 2, 2006, 26(31):8160-8167; doi:10.1523/JNEUROSCI.4809-05.2006

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (21) Citing Articles via Google Scholar Google Scholar Articles by Baglioni, S. Articles by Stefani, M. Search for Related Content PubMed PubMed Citation Articles by Baglioni, S. Articles by Stefani, M.

 Previous Article  |  Next Article 

Neurobiology of Disease
Prefibrillar Amyloid Aggregates Could Be Generic Toxins in Higher Organisms

Serena Baglioni,¹ Fiorella Casamenti,² Monica Bucciantini,^1,3 Leila M. Luheshi,⁴ Niccolò Taddei,^1,3 Fabrizio Chiti,¹ Christopher M. Dobson,⁴ and Massimo Stefani^1,3

¹Department of Biochemical Sciences, University of Florence, 50134 Florence, Italy, ²Department of Pharmacology, University of Florence, 50139 Florence, Italy, ³Interuniversity Centre for the Study of the Molecular Basis of Neurodegenerative Diseases and ⁴Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom

Correspondence should be addressed to either of the following: Prof. Massimo Stefani, Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy, Email: stefani{at}scibio.unifi.it; or Prof. Christopher M. Dobson, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK, Email: cmd44{at}cam.ac.uk

More than 40 human diseases are associated with fibrillar deposits of specific peptides or proteins in tissue. Amyloid fibrils, or their precursors, can be highly toxic to cells, suggesting their key role in disease pathogenesis. Proteins not associated with any disease are able to form oligomers and amyloid assemblies in vitro displaying structures and cytotoxicity comparable with those of aggregates of disease-related polypeptides. In isolated cells, such toxicity has been shown to result from increased membrane permeability with disruption of ion homeostasis and oxidative stress. Here we microinjected into the nucleus basalis magnocellularis of rat brains aggregates of an Src homology 3 domain and the N-terminal domain of the prokaryotic HypF, neither of which is associated with amyloid disease. Prefibrillar aggregates of both proteins, but not their mature fibrils or soluble monomers, impaired cholinergic neuron viability in a dose-dependent manner similar to that seen in cell cultures. Contrary to the situation with cultured cells, however, under our experimental conditions, cell stress in tissue is not followed by a comparable level of cell death, a result that is very likely to reflect the presence of protective mechanisms reducing aggregate toxicity. These findings support the hypothesis that neurodegenerative disorders result primarily from a generic cell dysfunction caused by early misfolded species in the aggregation process.

Key words: amyloid fibrils; cell dysfunction; neurodegenerative diseases; protein aggregation; protein misfolding; aggregate microinjection

---

Received Nov. 9, 2005; revised May 29, 2006; accepted May 31, 2006.

Correspondence should be addressed to either of the following: Prof. Massimo Stefani, Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy, Email: stefani{at}scibio.unifi.it; or Prof. Christopher M. Dobson, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK, Email: cmd44{at}cam.ac.uk

This article has been cited by other articles:

				T. Parasassi, M. De Spirito, G. Mei, R. Brunelli, G. Greco, L. Lenzi, G. Maulucci, E. Nicolai, M. Papi, G. Arcovito, et al. Low density lipoprotein misfolding and amyloidogenesis FASEB J, July 1, 2008; 22(7): 2350 - 2356. [Abstract] [Full Text] [PDF]

				Z. Ignatova, A. K. Thakur, R. Wetzel, and L. M. Gierasch In-cell Aggregation of a Polyglutamine-containing Chimera Is a Multistep Process Initiated by the Flanking Sequence J. Biol. Chem., December 14, 2007; 282(50): 36736 - 36743. [Abstract] [Full Text] [PDF]

				E. Sandelin, A. Nordlund, P. M. Andersen, S. S. L. Marklund, and M. Oliveberg Amyotrophic Lateral Sclerosis-associated Copper/Zinc Superoxide Dismutase Mutations Preferentially Reduce the Repulsive Charge of the Proteins J. Biol. Chem., July 20, 2007; 282(29): 21230 - 21236. [Abstract] [Full Text] [PDF]

				S. Linse, C. Cabaleiro-Lago, W.-F. Xue, I. Lynch, S. Lindman, E. Thulin, S. E. Radford, and K. A. Dawson From the Cover: Nucleation of protein fibrillation by nanoparticles PNAS, May 22, 2007; 104(21): 8691 - 8696. [Abstract] [Full Text] [PDF]

				X. Wang and J. Robbins Heart Failure and Protein Quality Control Circ. Res., December 8, 2006; 99(12): 1315 - 1328. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help