Diphenyl diselenide protects a Caenorhabditis elegans model for Huntington's disease by activation of the antioxidant...

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene.
• Protein aggregation and cellular dysfunction characterize HD, impacting proteostasis and homeostasis.
• Caenorhabditis elegans serves as a valuable model for studying neurodegenerative diseases due to genetic homology and manipulability.

Purpose of the Study:

• To investigate the therapeutic potential of diphenyl diselenide ((PhSe)2) in a Caenorhabditis elegans model of Huntington's disease.
• To evaluate the effects of (PhSe)2 on polyglutamine aggregation, neurodegeneration, and lifespan.
• To elucidate the underlying molecular mechanisms involving DAF-16 and downstream targets.

Main Methods:

• Exposure of wild-type and polyQ mutant Caenorhabditis elegans to varying concentrations of diphenyl diselenide (25, 50, 100 μM).
• Assessment of polyglutamine aggregation, neuronal cell death (ASH sensory neurons), touch response, reactive oxygen species (ROS) levels, lifespan, and health span.
• Analysis of the involvement of the transcription factor DAF-16 and its downstream effectors, heat-shock protein-16.2 (HSP-16.2) and superoxide dismutase-3 (SOD-3).

Main Results:

• Chronic diphenyl diselenide treatment significantly reduced polyglutamine aggregation in muscles and prevented polyglutamine-mediated neuronal cell death.
• (PhSe)2 treatment maintained neuronal function, decreased reactive oxygen species (ROS) levels, and extended both lifespan and health span in wild-type and mutant worms.
• The protective effects were associated with the activation of DAF-16, HSP-16.2, and SOD-3, enhancing antioxidant capacity and proteostasis.

Conclusions:

• Diphenyl diselenide demonstrates neuroprotective properties against polyglutamine toxicity in a Caenorhabditis elegans model.
• The mechanism involves the DAF-16/HSP-16.2/SOD-3 pathway, improving proteostasis and reducing oxidative stress.
• These findings suggest diphenyl diselenide as a potential therapeutic candidate for Huntington's disease and other protein aggregation disorders.