LRRK2 protects immune cells against erastin-induced ferroptosis

Oun, Asmaa; Soliman, Ahmed; Trombetta-Lima, Marina; Tzepapadaki, Afroditi; Tsagkari, Dikaia; Kortholt, Arjan; Dolga, Amalia M.

doi:10.1016/j.nbd.2022.105917

Cited by 13 publications

(9 citation statements)

References 76 publications

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“…Ferroptosis is defined by an increased build‐up of lipid peroxidation and reactive oxygen species originating from iron metabolism. Morphologically, it is characterized by unusually small mitochondria with denser mitochondrial membranes, and a reduction or disappearance of mitochondrial cristae 7,11,13,59 . Post ICH, brain injury is significantly caused by iron release from hemoglobin breakdown in hematomas, leading to ROS production.…”

Section: Discussionmentioning

confidence: 99%

“…Morphologically, it is characterized by unusually small mitochondria with denser mitochondrial membranes, and a reduction or disappearance of mitochondrial cristae. 7 , 11 , 13 , 59 Post ICH, brain injury is significantly caused by iron release from hemoglobin breakdown in hematomas, leading to ROS production. The presence of blood components from the hematoma activates immune cells, such as microglia, leading to an inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

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Attenuation of neuronal ferroptosis in intracerebral hemorrhage by inhibiting HDAC1/2: Microglial heterogenization via the Nrf2/HO1 pathway

Jiang,

Yang,

et al. 2024

CNS Neurosci Ther

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AimThe class I histone deacetylases (HDACs) implicate in microglial heterogenization and neuroinflammation following Intracerebral hemorrhage (ICH). Ferroptosis has also been reported in the ICH model. However, the relationship between HDAC1/2's role in microglial heterogenization and neuronal ferroptosis remains unclear.MethodsIn both in vivo and in vitro models of ICH, we used Romidepsin (FK228), a selective HDAC1/2 inhibitor, to investigate its effects on microglial heterogenization and neuronal ferroptosis. In the in vitro ICH model using Hemin, a transwell system was utilized to examine how microglia‐driven inflammation and ICH‐triggered neuronal ferroptosis interact. Immunostaining, Western blotting and RT‐qPCR were used to evaluate the microglial heterogenization and neuronal ferroptosis. Microglial heterogenization, neuronal ferroptosis, and neurological dysfunctions were assessed in vivo ICH mice model performed by autologous blood injection.ResultsHDAC1/2 inhibition altered microglial heterogenization after ICH, as showing the reducing neuroinflammation and shifting microglia towards an anti‐inflammatory phenotype by immunostaining and qPCR results. HDAC1/2 inhibition reduced ferroptosis, characterized by high ROS and low GPx4 expression in HT22 cells, and reduced iron and lipid deposition post‐ICH in vivo. Additionally, the Nrf2/HO1 signaling pathway, especially acetyl‐Nrf2, activated in the in vivo ICH model due to HDAC1/2 inhibition, plays a role in regulating microglial heterogenization. Furthermore, HDAC1/2 inhibition improved sensorimotor and histological outcomes post‐ICH, offering a potential mechanism against ICH.ConclusionInhibition of HDAC1/2 reduces neuro‐ferroptosis by modifying the heterogeneity of microglia via the Nrf2/HO1 pathway, with a particular focus on acetyl‐Nrf2. Additionally, this inhibition aids in the faster removal of hematomas and lessens prolonged neurological impairments, indicating novel approach for treating ICH.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Attenuation of neuronal ferroptosis in intracerebral hemorrhage by inhibiting HDAC1/2: Microglial heterogenization via the Nrf2/HO1 pathway

Jiang,

Yang,

et al. 2024

CNS Neurosci Ther

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“…In this context, many mechanisms have been proposed, including the presence of highly branched, poorly myelinated long axons, which are associated with mitochondrial oxidative stress, and large fluctuations in cytosolic calcium levels [ 101 ]. Another interesting process that has recently emerged in the literature is ferroptosis, an iron-dependent cell death pathway that involves the accumulation of lipid peroxidation accompanied by the concomitant depletion of intracellular GSH and that has been suggested as a contributing mechanism of neuronal death in PD [ 102 , 103 , 104 ]. This process is regulated in a complex way through the involvement of multiple enzymes, iron-binding proteins, and several transport systems.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress and Neuroinflammation in Parkinson’s Disease: The Role of Dopamine Oxidation Products

Chakrabarti

Bisaglia

2023

Antioxidants

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Parkinson’s disease (PD) is a chronic neurodegenerative condition affecting more than 1% of people over 65 years old. It is characterized by the preferential degeneration of nigrostriatal dopaminergic neurons, which is responsible for the motor symptoms of PD patients. The pathogenesis of this multifactorial disorder is still elusive, hampering the discovery of therapeutic strategies able to suppress the disease’s progression. While redox alterations, mitochondrial dysfunctions, and neuroinflammation are clearly involved in PD pathology, how these processes lead to the preferential degeneration of dopaminergic neurons is still an unanswered question. In this context, the presence of dopamine itself within this neuronal population could represent a crucial determinant. In the present review, an attempt is made to link the aforementioned pathways to the oxidation chemistry of dopamine, leading to the formation of free radical species, reactive quinones and toxic metabolites, and sustaining a pathological vicious cycle.

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“…The G2019S-LRRK2 mutation is the most common causative genetic factor linked to PD because of abnormally elevated kinase activity [ 12 , 26 ]. Recently, it was reported that a G2019S knock-in significantly increased the iron deposition in proinflammatory conditions, focusing on microglia but not neurons or other types of cells and indirectly describing the effect of LRRK2 on iron absorption [ 27 , 28 ]. Our study provides direct evidence that overexpression of LRRK2 increased cellular uptake of FAS; moreover, G2019S-LRRK2 mutant cells with high kinase activity showed the strongest absorption capacity for ferrous iron among the WT-LRRK2, G2019S-LRRK2, and D2017A-LRRK2 groups ( Figure 5 C).…”

Section: Discussionmentioning

confidence: 99%

The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model

Jia

Liu

Shuai

et al. 2023

IJMS

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The pathogenesis of Parkinson’s disease (PD) is very complex and still needs further exploration. Leucine-rich repeat kinase 2 (LRRK2) is associated with familial PD in mutant forms and sporadic PD in the wild-type form. Abnormal iron accumulation is found in the substantia nigra of PD patients, but its exact effects are not very clear. Here, we show that iron dextran exacerbates the neurological deficit and loss of dopaminergic neurons in 6-OHDA lesioned rats. 6-OHDA and ferric ammonium citrate (FAC) significantly increase the activity of LRRK2 as reflected by the phosphorylation of LRRK2, at S935 and S1292 sites. 6-OHDA-induced LRRK2 phosphorylation is attenuated by the iron chelator deferoxamine, especially at the S1292 site. 6-OHDA and FAC markedly induce the expression of pro-apoptotic molecules and the production of ROS by activating LRRK2. Furthermore, G2019S-LRRK2 with high kinase activity showed the strongest absorptive capacity for ferrous iron and the highest intracellular iron content among WT-LRRK2, G2019S-LRRK2, and kinase-inactive D2017A-LRRK2 groups. Taken together, our results demonstrate that iron promotes the activation of LRRK2, and active LRRK2 accelerates ferrous iron uptake, suggesting that there exists an interplay between iron and LRRK2 in dopaminergic neurons, providing a new perspective to uncover the underlying mechanisms of PD occurrence.

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LRRK2 protects immune cells against erastin-induced ferroptosis

Cited by 13 publications

References 76 publications

Attenuation of neuronal ferroptosis in intracerebral hemorrhage by inhibiting HDAC1/2: Microglial heterogenization via the Nrf2/HO1 pathway

Attenuation of neuronal ferroptosis in intracerebral hemorrhage by inhibiting HDAC1/2: Microglial heterogenization via the Nrf2/HO1 pathway

Oxidative Stress and Neuroinflammation in Parkinson’s Disease: The Role of Dopamine Oxidation Products

The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model

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