Hsp104 antagonizes α-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease

Christophe Lo Bianco, James Shorter, Etienne Régulier, Hilal Lashuel, Takeshi Iwatsubo, Susan Lindquist, Patrick Aebischer

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

Parkinson disease (PD) is characterized by dopaminergic neurodegeneration and intracellular inclusions of α-synuclein amyloid fibers, which are stable and difficult to dissolve. Whether inclusions are neuroprotective or pathological remains controversial, because prefibrillar oligomers may be more toxic than amyloid inclusions. Thus, whether therapies should target inclusions, preamyloid oligomers, or both is a critically important issue. In yeast, the protein-remodeling factor Hsp104 cooperates with Hsp70 and Hsp40 to dissolve and reactivate aggregated proteins. Metazoans, however, have no Hsp104 ortholog. Here we introduced Hsp104 into a rat PD model. Remarkably, Hsp104 reduced formation of phosphorylated α-synuclein inclusions and prevented nigrostriatal dopaminergic neurodegeneration induced by PD-linked α-synuclein (A30P). An in vitro assay employing pure proteins revealed that Hsp104 prevented fibrillization of α-synuclein and PD-linked variants (A30P, A53T, E46K). Hsp104 coupled ATP hydrolysis to the disassembly of preamyloid oligomers and amyloid fibers composed of α-synuclein. Furthermore, the mammalian Hsp70 and Hsp40 chaperones, Hsc70 and Hdj2, enhanced α-synuclein fiber disassembly by Hsp104. Hsp104 likely protects dopaminergic neurons by antagonizing toxic α-synuclein assemblies and might have therapeutic potential for PD and other neurodegenerative amyloidoses.

Original languageEnglish
Pages (from-to)3087-3097
Number of pages11
JournalJournal of Clinical Investigation
Volume118
Issue number9
DOIs
Publication statusPublished - 2 Sep 2008
Externally publishedYes

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Synucleins
Parkinson Disease
Amyloid
Poisons
Proteins
Dopaminergic Neurons
Amyloidosis
Hydrolysis
Adenosine Triphosphate
Yeasts

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lo Bianco, C., Shorter, J., Régulier, E., Lashuel, H., Iwatsubo, T., Lindquist, S., & Aebischer, P. (2008). Hsp104 antagonizes α-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease. Journal of Clinical Investigation, 118(9), 3087-3097. https://doi.org/10.1172/JCI35781

Hsp104 antagonizes α-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease. / Lo Bianco, Christophe; Shorter, James; Régulier, Etienne; Lashuel, Hilal; Iwatsubo, Takeshi; Lindquist, Susan; Aebischer, Patrick.

In: Journal of Clinical Investigation, Vol. 118, No. 9, 02.09.2008, p. 3087-3097.

Research output: Contribution to journalArticle

Lo Bianco, C, Shorter, J, Régulier, E, Lashuel, H, Iwatsubo, T, Lindquist, S & Aebischer, P 2008, 'Hsp104 antagonizes α-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease', Journal of Clinical Investigation, vol. 118, no. 9, pp. 3087-3097. https://doi.org/10.1172/JCI35781
Lo Bianco, Christophe ; Shorter, James ; Régulier, Etienne ; Lashuel, Hilal ; Iwatsubo, Takeshi ; Lindquist, Susan ; Aebischer, Patrick. / Hsp104 antagonizes α-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 9. pp. 3087-3097.
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