Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is caused by selective degeneration of motor neurons in the brain and spinal cord; however, the primary cell death pathway(s) mediating motor neuron demise remain elusive. We recently established that necroptosis, an inflammatory form of regulated cell death, was dispensable for motor neuron death in a mouse model of ALS, implicating other forms of cell death. Here, we confirm these findings in ALS patients, showing a lack of expression of key necroptotic effector proteins in spinal cords. Rather, we uncover evidence for ferroptosis, a recently discovered iron-dependent form of regulated cell death, in ALS. Depletion of glutathione peroxidase 4 (GPX4), an anti-oxidant enzyme and central repressor of ferroptosis, occurred in post-mortem spinal cords of both sporadic and familial ALS patients. GPX4 depletion was also an early and universal feature of spinal cords and brains of transgenic mutant superoxide dismutase 1 (SOD1(G93A)), TDP-43 and C9orf72 mouse models of ALS. GPX4 depletion and ferroptosis were linked to impaired NRF2 signalling and dysregulation of glutathione synthesis and iron-binding proteins. Novel BAC transgenic mice overexpressing human GPX4 exhibited high GPX4 expression localised to spinal motor neurons. Human GPX4 overexpression in SOD1(G93A) mice significantly delayed disease onset, improved locomotor function and prolonged lifespan, which was attributed to attenuated lipid peroxidation and motor neuron preservation. Our study discovers a new role for ferroptosis in mediating motor neuron death in ALS, supporting the use of anti-ferroptotic therapeutic strategies, such as GPX4 pathway induction and upregulation, for ALS treatment.

Automated summary

Amyotrophic lateral sclerosis (ALS) is characterized by selective degeneration of motor neurons in the brain and spinal cord, with recent findings suggesting a role for ferroptosis, an iron-dependent form of regulated cell death, in mediating motor neuron death in ALS. Depletion of the antioxidant enzyme GPX4, a central repressor of ferroptosis, was observed in post-mortem spinal cords of ALS patients and in various ALS mouse models, linking GPX4 depletion and ferroptosis to impaired NRF2 signaling and dysregulation of glutathione synthesis and iron-binding proteins. Overexpression of human GPX4 in ALS mice delayed disease onset, improved locomotor function, and prolonged lifespan, demonstrating the potential for anti-ferroptotic therapeutic strategies for ALS treatment.