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

Abstract

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.

Brain Iron Metabolism, Redox Balance and Neurological Diseases

“…FAC can catalyze the phosphorylation of S935 and S1292 of LRRK2, significantly increasing its activity. Active LRRK2 accelerates ferrous iron uptake, indicating a relationship between iron and LRRK2 in dopaminergic neurons [ 151 ].…”

ACSL4-Mediated Ferroptosis and Its Potential Role in Central Nervous System Diseases and Injuries

“…Through the assessment of PD patients, it has been observed that the iron content in glial and dopaminergic neurons is abnormally elevated compared to that in healthy individuals, and this elevation is positively associated with the severity of PD [ 108 , 109 , 110 ]. Research has identified the formation of Lewy bodies, composed mainly of α-synuclein nucleoprotein [ 111 , 112 ], as a distinctive hallmark of PD, occurring within the cytoplasm of substantia nigra neurons [ 113 , 114 ].…”

Special Issue ‘Advances in Neurodegenerative Diseases Research and Therapy 2.0’

“…Traditionally, it has been difficult to treat a disease without proper knowledge of the underlying etiologies. In view of this, Sheu et al [12] and Jia et al [13] reported novel underlying molecular changes occurring in different situations within NDs. Although the BBB has been associated in protecting the brain from peripheral insults, BBB disruption occurs during various stages of different NDs [19], and this may allow molecules like thrombin to invade brain tissue.…”

“…Some of the major obstacles in the field of ND therapy and disease management include limited therapeutic options, especially due to ineffective drug delivery methods; unknown etiological factors; and complications from other concurrent pathological conditions [8][9][10]. The research work presented in this Special Issue encompasses various aspects of these obstacles in ND research and presents novel aspects of drug delivery [11], molecular mechanisms associated with ND etiologies [12,13], the molecular pathways shared between diseases [14,15], and therapeutic approaches [16,17].…”