ALOX5-mediated ferroptosis acts as a distinct cell death pathway upon oxidative stress in Huntington's disease

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Huntington's disease (HD) pathogenesis is linked to mutant huntingtin (mHTT).
• The precise molecular mechanisms driving mHTT-induced cellular damage, particularly ferroptosis, remain incompletely understood.
• Ferroptosis, a regulated form of cell death, has emerged as a key process in neurodegenerative diseases.

Purpose of the Study:

• To elucidate the molecular pathways by which mutant huntingtin (mHTT) induces ferroptosis.
• To identify novel factors involved in mHTT-mediated ferroptosis.
• To evaluate the therapeutic potential of targeting these factors in Huntington's disease.

Main Methods:

• Expression of N-terminal mutant huntingtin fragment (HTTQ94) in cellular and mouse models.
• RNA interference (RNAi)-mediated genetic screening to identify key regulatory genes.
• Assessment of ferroptosis markers, reactive oxygen species (ROS) levels, and cell viability.
• Analysis of gene and protein expression, including FLAP stabilization.
• Evaluation of pathological phenotypes and lifespan in Huntington's disease mouse models.

Main Results:

• HTTQ94 induced both ACSL4-dependent and ACSL4-independent ferroptosis.
• Inactivation of ACSL4-dependent ferroptosis did not affect the lifespan of HD mice.
• RNAi screening identified ALOX5 as crucial for HTTQ94-induced ACSL4-independent ferroptosis.
• ALOX5, but not common ferroptosis inducers, mediated ferroptosis upon ROS or glutamate stress in HD models.
• HTTQ94 stabilized FLAP, activating ALOX5-mediated ferroptosis.
• Loss of ALOX5 ameliorated pathological phenotypes and extended lifespan in HD mice.

Conclusions:

• ALOX5 is a critical mediator of mutant huntingtin-induced ferroptosis.
• Targeting ALOX5 presents a promising therapeutic strategy for Huntington's disease.
• Understanding the role of ALOX5 in ferroptosis opens new avenues for HD treatment.