Restoration of c-Src/Fyn Proteins Rescues Mitochondrial Dysfunction in Huntington's Disease

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Huntington's disease (HD) is a neurodegenerative disorder with no cure.
• Mutant huntingtin protein (mHTT) causes mitochondrial dysfunction and reactive oxygen species (ROS) production.
• The role of Src-related kinases (c-Src and Fyn) in HD pathogenesis is unknown.

Purpose of the Study:

• To investigate changes in c-Src/Fyn proteins in HD models.
• To explore the role of c-Src/Fyn in mitochondrial dysfunction and redox imbalance in HD.
• To identify potential therapeutic targets for HD.

Main Methods:

• Analysis of c-Src/Fyn protein levels and activation in human and mouse HD models.
• Assessment of mitochondrial function, morphology, and dynamics.
• Evaluation of ROS levels and autophagy induction.
• Restoration of active c-Src/Fyn levels in HD models.

Main Results:

• c-Src/Fyn levels and activation are decreased in HD models due to autophagy degradation.
• mHTT expression enhances TFEB-mediated autophagy induction and flux.
• Restoring active c-Src/Fyn improves mitochondrial morphology and function (membrane potential, respiration, ATP production).
• Active c-Src/Fyn reduces ROS levels in mHTT-expressing cells.

Conclusions:

• c-Src/Fyn proteins play a critical role in regulating mitochondrial function and redox balance in HD.
• Restoration of c-Src/Fyn activity is a promising therapeutic strategy for HD.
• Targeting c-Src/Fyn may ameliorate mitochondrial dysfunction and oxidative stress in Huntington's disease.