[Unfolding chaperone as a prion protein relating molecule]

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Prion diseases like mad cow disease are caused by misfolded prion protein (PrPSc) isoforms.
• Cellular prion protein (PrPc) and PrPSc share identical amino acid sequences but differ in conformation.
• A host factor, potentially a molecular chaperone, may facilitate the conformational change from PrPc to PrPSc.

Purpose of the Study:

• To investigate the existence and function of a molecular chaperone capable of unfolding misfolded protein structures.
• To identify and characterize a novel chaperone with potential activity against prion protein.

Main Methods:

• Construction of an assay system to detect protein unfolding activity.
• Purification of a novel molecular chaperone from S. cerevisiae.
• Testing the chaperone's activity against various misfolded proteins, including beta-sheet rich PrP, alpha-synuclein, and A beta.
• Assessing the role of ATP and identifying the chaperone's oligomeric structure.

Main Results:

• A novel molecular chaperone with broad-spectrum protein unfolding activity was purified from S. cerevisiae.
• The chaperone demonstrated ATP-dependent activity against beta-sheet rich PrP, alpha-synuclein, and A beta.
• The chaperone possesses an oligomeric ring-like structure with a central cavity.
• Activity was reduced by ATP hydrolysis, confirming its ATP-dependent nature and oligomeric assembly (4-5 subunits).

Conclusions:

• A novel ATP-dependent molecular chaperone with protein unfolding capabilities has been identified.
• This chaperone effectively targets misfolded prion protein and other aggregation-prone proteins.
• The findings suggest a potential therapeutic target for prion and other neurodegenerative diseases.