1. Academic Validation
  2. ALOX5-mediated ferroptosis acts as a distinct cell death pathway upon oxidative stress in Huntington's disease

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

  • Genes Dev. 2023 Mar 15. doi: 10.1101/gad.350211.122.
Shujuan Song # 1 2 Zhenyi Su # 1 Ning Kon 1 Bo Chu 1 Huan Li 1 Xuejun Jiang 3 Jianyuan Luo 2 Brent R Stockwell 4 Wei Gu 5
Affiliations

Affiliations

  • 1 Institute for Cancer Genetics, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York 10032, USA.
  • 2 Department of Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 3 Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
  • 4 Department of Biological Sciences, Department of Chemistry, Columbia University, New York, New York 10027, USA.
  • 5 Institute for Cancer Genetics, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York 10032, USA; wg8@cumc.columbia.edu.
  • # Contributed equally.
Abstract

Although it is well established that Huntington's disease (HD) is mainly caused by polyglutamine-expanded mutant Huntingtin (mHTT), the molecular mechanism of mHTT-mediated actions is not fully understood. Here, we showed that expression of the N-terminal fragment containing the expanded polyglutamine (HTTQ94) of mHTT is able to promote both the ACSL4-dependent and the ACSL4-independent Ferroptosis. Surprisingly, inactivation of the ACSL4-dependent Ferroptosis fails to show any effect on the life span of Huntington's disease mice. Moreover, by using RNAi-mediated screening, we identified ALOX5 as a major factor required for the ACSL4-independent Ferroptosis induced by HTTQ94. Although ALOX5 is not required for the ferroptotic responses triggered by common Ferroptosis inducers such as erastin, loss of ALOX5 expression abolishes HTTQ94-mediated Ferroptosis upon Reactive Oxygen Species (ROS)-induced stress. Interestingly, ALOX5 is also required for HTTQ94-mediated Ferroptosis in neuronal cells upon high levels of glutamate. Mechanistically, HTTQ94 activates ALOX5-mediated Ferroptosis by stabilizing FLAP, an essential cofactor of ALOX5-mediated Lipoxygenase activity. Notably, inactivation of the Alox5 gene abrogates the Ferroptosis activity in the striatal neurons from the HD mice; more importantly, loss of ALOX5 significantly ameliorates the pathological phenotypes and extends the life spans of these HD mice. Taken together, these results demonstrate that ALOX5 is critical for mHTT-mediated Ferroptosis and suggest that ALOX5 is a potential new target for Huntington's disease.

Keywords

ACSL4; ALOX5; GPX4; HTT; ROS; ferroptosis; oxidative stress.

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