Skip to Main content Skip to Navigation

Critical Role of the Proline-rich Region in Huntingtin for Aggregation and Cytotoxicity in Yeast

Abstract : Nine neurodegenerative diseases, such as Huntington, are caused by a polyglutamine (poly(Q)) expansion in otherwise unrelated proteins. Although poly(Q) expansion causes aggregation of the affected proteins, the protein context might determine the selective neuronal vulnerability found in each disease. Here we have report that, although expression of Huntingtin derivatives with a pathological poly(Q) expansion are innocuous in yeast, deletion of the flanking proline-rich region alters the shape and number of poly(Q) inclusions and unmasks toxic properties. Strikingly, deletion of Hsp104 increases the size of inclusions formed by expanded poly(Q) lacking the proline-rich region and abolishes toxicity. Overexpression of the chaperones Hsp104 or Hsp70 rescues growth defects in affected cells without resolving inclusions. However, aggregates formed by nontoxic Huntingtin derivatives or by toxic derivatives cured by chaperones are physically distinct from aggregates formed by toxic proteins. This study identifies the proline-rich region in Huntingtin as a profound cis-acting modulator of expanded poly(Q) toxicity and distinguishes between aggregates of toxic or non-toxic proteins.
Document type :
Journal articles
Complete list of metadatas

Cited literature [39 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-02439167
Contributor : Benjamin Dehay <>
Submitted on : Tuesday, January 14, 2020 - 2:56:26 PM
Last modification on : Friday, January 17, 2020 - 1:36:48 AM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

Benjamin Dehay, Anne Bertolotti. Critical Role of the Proline-rich Region in Huntingtin for Aggregation and Cytotoxicity in Yeast. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2006, 281 (47), pp.35608-35615. ⟨10.1074/jbc.M605558200⟩. ⟨inserm-02439167⟩

Share

Metrics

Record views

23