Evidence of Oxytosis/Ferroptosis in Niemann-Pick Disease Type C.

Niemann-Pick Disease Type C (NPC) is a hereditary neurodegenerative disease characterized by selective cell vulnerability, particularly affecting cerebellar anterior Purkinje neurons. These neurons exhibit a distinctive pattern of degeneration due to the loss of NPC1 and/or NPC2 protein function, progressively extending towards posterior cerebellar regions. Our study aimed to explore the early factors influencing this selective vulnerability of anterior Purkinje neurons in NPC. Oxytosis/ferroptosis, a novel form of regulated cell death, has been implicated in neurodegenerative diseases, with its inhibition showing promising therapeutic potential. Our laboratory has previously identified parallels between NPC cellular pathology and ferroptotic markers, including elevated levels of lipid peroxidation and iron, mitochondrial dysfunction, and Ca2+ dyshomeostasis. However, whether oxytosis/ferroptosis underlies NPC cellular pathology remains unexplored. We hypothesize that loss of NPC1 function increases vulnerability to ferroptosis and that anti-ferroptotic compounds will reverse NPC cellular pathology. Through bioinformatic analyses of pre-symptomatic Npc1-/- Purkinje neurons and in vitro studies using primary dermal fibroblasts derived from NPC patients, we provide evidence suggesting that oxytosis/ferroptosis may play a pathogenic role in NPC. These findings highlight the potential of anti-ferroptotic compounds as a promising therapeutic strategy to mitigate neurodegeneration in NPC and potentially other related disorders.