Dissociation of amyloid fibrils of α-synuclein and transthyretin by pressure reveals their reversible nature and the formation of water-excluded cavities

Débora Foguel, Marisa C. Suarez, Astria D. Ferrão-Gonzales, Thais C R Porto, Leonardo Palmieri, Carla M. Einsiedler, Leonardo R. Andrade, Hilal A. Lashuel, Peter T. Lansbury, Jeffery W. Kelly, Jerson L. Silva

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

Protein misfolding and aggregation have been linked to several human diseases, including Alżheimer's disease, Parkinson's disease, and systemic amyloidosis, by mechanisms that are not yet completely understood. The hallmark of most of these diseases is the formation of highly ordered and β-sheet-rich aggregates referred to as amyloid fibrils. Fibril formation by WT transthyretin (TTR) or TTR variants has been linked to the etiology of systemic amyloidosis and familial amyloid polyneuropathy, respectively. Similarly, amyloid fibril formation by α-synuclein (α-syn) has been linked to neurodegeneration in Parkinson's disease, a movement disorder characterized by selective degeneration of dopaminergic neurons in the substantia nigra. Here we show that consecutive cycles of compression-decompression under aggregating conditions lead to reversible dissociation of TTR and α-syn fibrils. The high sensitivity of amyloid fibrils toward high hydrostatic pressure (HHP) indicates the existence of packing defects in the fibril core. In addition, through the use of HHP we are able to detect differences in stability between fibrils formed from WT TTR and the familial amyloidotic polyneuropathy-associated variant V30M. The fibrils formed by VVT α-syn were less susceptible to pressure denaturation than the Parkinson's disease-linked variants, A30P and A53T. This finding implies that fibrils of α-syn formed from the variants would be more easily dissolved into small oligomers by the cellular machinery. This result has physiological importance in light of the current view that the pathogenic species are the small aggregates rather the mature fibrils. Finally, the HHP-induced formation of fibrils from TTR is relatively fast (≈60 min), a quality that allows screening of antiamyloidogenic drugs.

Original languageEnglish
Pages (from-to)9831-9836
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number17
DOIs
Publication statusPublished - 19 Aug 2003
Externally publishedYes

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Synucleins
Prealbumin
Amyloid
Hydrostatic Pressure
Pressure
Water
Parkinson Disease
Amyloidosis
Familial Amyloid Neuropathies
Preclinical Drug Evaluations
Polyneuropathies
Dopaminergic Neurons
Movement Disorders
Substantia Nigra
Decompression
Proteins

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Dissociation of amyloid fibrils of α-synuclein and transthyretin by pressure reveals their reversible nature and the formation of water-excluded cavities. / Foguel, Débora; Suarez, Marisa C.; Ferrão-Gonzales, Astria D.; Porto, Thais C R; Palmieri, Leonardo; Einsiedler, Carla M.; Andrade, Leonardo R.; Lashuel, Hilal A.; Lansbury, Peter T.; Kelly, Jeffery W.; Silva, Jerson L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 17, 19.08.2003, p. 9831-9836.

Research output: Contribution to journalArticle

Foguel, D, Suarez, MC, Ferrão-Gonzales, AD, Porto, TCR, Palmieri, L, Einsiedler, CM, Andrade, LR, Lashuel, HA, Lansbury, PT, Kelly, JW & Silva, JL 2003, 'Dissociation of amyloid fibrils of α-synuclein and transthyretin by pressure reveals their reversible nature and the formation of water-excluded cavities', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 17, pp. 9831-9836. https://doi.org/10.1073/pnas.1734009100
Foguel, Débora ; Suarez, Marisa C. ; Ferrão-Gonzales, Astria D. ; Porto, Thais C R ; Palmieri, Leonardo ; Einsiedler, Carla M. ; Andrade, Leonardo R. ; Lashuel, Hilal A. ; Lansbury, Peter T. ; Kelly, Jeffery W. ; Silva, Jerson L. / Dissociation of amyloid fibrils of α-synuclein and transthyretin by pressure reveals their reversible nature and the formation of water-excluded cavities. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 17. pp. 9831-9836.
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AU - Ferrão-Gonzales, Astria D.

AU - Porto, Thais C R

AU - Palmieri, Leonardo

AU - Einsiedler, Carla M.

AU - Andrade, Leonardo R.

AU - Lashuel, Hilal A.

AU - Lansbury, Peter T.

AU - Kelly, Jeffery W.

AU - Silva, Jerson L.

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