Integrated multi-omics analysis of Huntington disease identifies pathways that modulate protein aggregation

Area of Science:

• Neuroscience
• Genetics
• Metabolomics

Background:

• Huntington disease (HD) is a neurodegenerative disorder caused by polyglutamine expansion in huntingtin (HTT).
• While repeat length correlates with disease onset, other factors (disease modifiers) influence HD's complexity.
• Mitochondrial dysfunction and metabolic deregulation are implicated in HD, but their mechanisms are unclear.

Purpose of the Study:

• To elucidate pathways modulating protein aggregation in Huntington disease.
• To analyze multi-omics data and validate findings using a yeast model.
• To identify common and unique deregulated pathways across human, mouse, and yeast models.

Main Methods:

• Comparative metabolomics analysis of HD patients and a yeast HD model.
• Systems analysis of multi-omics data from human, mouse, and yeast models.
• Experimental validation in a yeast model by altering metabolites and gene knockouts in deregulated pathways.

Main Results:

• Significant overlap in deregulated metabolic pathways between HD patients and the yeast model.
• Identification of common and unique deregulated pathways (amino acid metabolism, glutathione metabolism, longevity, autophagy, mitophagy) across species.
• Demonstration that modulating these pathways in yeast affects protein aggregation.

Conclusions:

• Metabolic and autophagy pathways significantly influence protein aggregation in Huntington disease.
• These findings have implications for understanding HD progression and prognosis.
• Targeting deregulated pathways presents a potential therapeutic strategy for Huntington disease.