New insights on neurodegeneration triggered by iron accumulation: Intersections with neutral lipid metabolism, ferroptosis, and motor impairment

MANISCALCHI, A.; BENZI JUNCOS, O.N.; CONDE, M.; FUNK, M.I.; FERMENTO, M.E.; FACCHINETTI, M.M.; CURINO, A.; URANGA, R.; ALZA, N.P.; SALVADOR, G.

Redox Biology

Elsevier BV

Año: 2024 vol. 71

2213-2317

Brain iron accumulation constitutes a pathognomonic indicator in several neurodegenerative disorders. Metalaccumulation associated with dopaminergic neuronal death has been documented in Parkinson’s disease.Through the use of in vivo and in vitro models, we demonstrated that lipid dysregulation manifests as a neuronaland glial response during iron overload.In this study, we show that cholesterol content and triacylglycerol (TAG) hydrolysis were strongly elevated inmice midbrain. Lipid cacostasis was concomitant with the loss of dopaminergic neurons, astrogliosis and elevatedexpression of α-synuclein. Exacerbated lipid peroxidation and markers of ferroptosis were evident in themidbrain from mice challenged with iron overload. An imbalance in the activity of lipolytic and acylation enzymeswas identified, favoring neutral lipid hydrolysis, and consequently reducing TAG and cholesteryl esterlevels. Notably, these observed alterations were accompanied by motor impairment in iron-treated mice.In addition, neuronal and glial cultures along with their secretomes were used to gain further insight into themechanism underlying TAG hydrolysis and cholesterol accumulation as cellular responses to iron accumulation.We demonstrated that TAG hydrolysis in neurons is triggered by astrocyte secretomes. Moreover, we found thatthe ferroptosis inhibitor, ferrostatin-1, effectively prevents cholesterol accumulation both in neurons and astrocytes.Taken together, these results indicate that lipid disturbances occur in iron-overloaded mice as aconsequence of iron-induced oxidative stress and depend on neuron-glia crosstalk. Our findings suggest thatdeveloping therapies aimed at restoring lipid homeostasis may lead to specific treatment for neurodegenerationassociated with ferroptosis and brain iron accumulation.