Hsp110 mitigates α-synuclein pathology in vivo.

Area of Science:

• Neuroscience
• Molecular Biology
• Protein Biochemistry

Background:

• Parkinson's disease involves alpha-synuclein aggregation into Lewy bodies.
• Mechanisms for disaggregating alpha-synuclein are not well understood.
• Molecular chaperones are investigated for their role in protein aggregation.

Purpose of the Study:

• To investigate the role of molecular chaperones, specifically the Hsp110 disaggregase complex, in preventing and disaggregating alpha-synuclein.
• To determine if Hsp110 can mitigate alpha-synuclein pathology in cellular and animal models.

Main Methods:

• Utilized mammalian cell culture models to assess alpha-synuclein aggregation with Hsp110 overexpression.
• Developed and analyzed transgenic Hsp110 and alpha-synuclein/Hsp110 double-transgenic mouse models.
• Performed unbiased synaptic proteome analysis in mouse models.
• Injected aggregated alpha-synuclein seeds into mouse brains to study templating and spread.

Main Results:

• Overexpression of Hsp110 reduced alpha-synuclein aggregation in cell culture.
• Hsp110 overexpression mitigated alpha-synuclein pathology in vivo in mouse models.
• Hsp110 overexpression reversed protein changes induced by the alpha-synuclein transgene.
• Hsp110 prevented endogenous alpha-synuclein templating and spread in the brain.

Conclusions:

• Hsp110 plays a significant role in preventing and/or disaggregating alpha-synuclein pathology.
• Hsp110 is a potential therapeutic target for Parkinson's disease.
• The mammalian disaggregase complex, including Hsp110, is crucial for maintaining protein homeostasis in the context of neurodegenerative diseases.