Alpha lipoic acid ameliorates motor deficits by inhibiting ferroptosis in Parkinson’s disease

A A., W C., N N., L M., M D., Zhang D.D.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting millions each year. Most PD cases (∼90%) are sporadic, resulting from the age-dependent accumulation of pathogenic effects. One key pathological hallmark of PD progression is the accumulation of alpha-synuclein (α-syn), which has been shown to negatively affect neuronal function and viability. Here, using 3- and 6-month-old Nrf2+/+ and Nrf2-/- mice overexpressing human α-syn (PD model), we show that loss of NRF2 increases markers of ferroptosis across PD-relevant brain regions. Increased ferroptosis was associated with an age- and genotype-dependent increase in α-syn pathology and behavioral deficits. Finally, we demonstrate that α-syn overexpression sensitizes neuronal cells and ex vivo brain slices to ferroptosis induction, which may be due to α-syn decreasing NRF2 protein levels. Altogether, these results indicate that NRF2 is a critical anti-ferroptotic mediator of neuronal survival, and that the vicious cycle of α-syn overexpression and NRF2 suppression, leading to enhanced neuronal ferroptotic cell death, could represent a targetable and currently untapped means of preventing PD onset and progression.

Wang Z., Yuan L., Li W., Li J.

Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron loss and the formation of cytoplasmic protein inclusions. Although the exact pathogenesis of PD is unknown, iron dyshomeostasis has been proposed as a potential contributing factor. Emerging evidence suggests that glial cell activation plays a pivotal role in ferroptosis and subsequent neurodegeneration. We review the association between iron deposition, glial activation, and neuronal death, and discuss whether and how ferroptosis affects α-synuclein aggregation and DA neuron loss. We examine the possible roles of different types of glia in mediating ferroptosis in neurons. Lastly, we review current PD clinical trials targeting iron homeostasis. Although clinical trials are already evaluating ferroptosis modulation in PD, much remains unknown about metal ion metabolism and regulation in PD pathogenesis.

Qiongyue Z., Xin Y., Meng P., Sulin M., Yanlin W., Xinyi L., Xuemin S.

Kidney is one of the most vulnerable organs in sepsis, resulting in sepsis-associated acute kidney injury (SA-AKI), which brings about not only morbidity but also mortality of sepsis. Ferroptosis is a new kind of death type of cells elicited by iron-dependent lipid peroxidation, which participates in pathogenesis of sepsis. The aim of this study was to verify the occurrence of ferroptosis in the SA-AKI pathogenesis and demonstrate that post-treatment with irisin could restrain ferroptosis and alleviate SA-AKI via activating the SIRT1/Nrf2 signaling pathway. We established a SA-AKI model by cecal ligation and puncture (CLP) operation and an in vitro model in LPS-induced HK2 cells, respectively. Our result exhibited that irisin inhibited the level of ferroptosis and ameliorated kidney injury in CLP mice, as evidenced by reducing the ROS production, iron content, and MDA level and increasing the GSH level, as well as the alteration of ferroptosis-related protein (GPX4 and ACSL4) expressions in renal, which was consistent with the ferroptosis inhibitor ferrostatin-1 (Fer-1). Additionally, we consistently observed that irisin inhibited ROS accumulation, iron production, and ameliorated mitochondrial dysfunction in LPS-stimulated HK-2 cells. Furthermore, our result also revealed that irisin could activate SIRT1/Nrf2 signaling pathways both in vivo and vitro. However, the beneficial effects of irisin were weakened by EX527 (an inhibitor of SIRT1) in vivo and by SIRT1 siRNA in vitro. In conclusion, irisin could protect against SA-AKI through ferroptotic resistance via activating the SIRT1/Nrf2 signaling pathway.

Zhang J., Gao Y., Zhang L., Zhang C., Zhao Y., Zhang Y., Li S., Chang C., Zhang X., Yang G.

Accumulated oxidative damage plays key roles in the pathogenesis of Parkinson’s disease (PD). Silent mating type information regulation 2 homolog 1 (SIRT1), a class III histone deacetylase, can directly activate peroxisome proliferator-activated receptor-c coactivator-1α (PGC-1α) and attenuate oxidative stress. Alpha-lipoic acid (ALA) is a natural antioxidant that has been demonstrated to protect PC12 cells against 1-methyl-4-phenylpyridinium (MPP+). However, the underlying mechanisms related to changes in cell signaling cascades are not fully understood. In the present study, the neuroprotective effect of ALA and the potential role of ALA in the SIRT1 pathway was investigated in vitro and in a mouse model of PD. A Cell Counting Kit-8 (CCK-8) assay was performed to detect the SY5Y-SH cell viability. Immunohistochemistry, quantitative real-time polymerase chain reaction and western blot assays were used to evaluate the expression of tyrosine hydroxylase (TH), SIRT1, and PGC-1α in vivo and in vitro. Intracellular reactive oxygen species (ROS) production and tissue SOD and MDA were detected by the corresponding assay kits. The results showed that ALA notably prevented oxidative stress and neurotoxicity in vivo and in vitro against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)/MPP+. Furthermore, ALA significantly increased the expression of SIRT1 and PGC-1α in vivo and in vitro in MPTP/MPP+-induced models, which was reversed by the SIRT1 inhibitor EX527. These results suggested that ALA prevented oxidative stress and that neurotoxicity was involved in the upregulation of SIRT1 and PGC-1α in PD mice.

Cheng R., Dhorajia V.V., Kim J., Kim Y.

Iron is a key element for mitochondrial function and homeostasis, which is also crucial for maintaining the neuronal system, but too much iron promotes oxidative stress. A large body of evidence has indicated that abnormal iron accumulation in the brain is associated with various neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. However, it is still unclear how irregular iron status contributes to the development of neuronal disorders. Hence, the current review provides an update on the causal effects of iron overload in the development and progression of neurodegenerative diseases and discusses important roles of mitochondrial iron homeostasis in these disease conditions. Furthermore, this review discusses potential therapeutic targets for the treatments of iron overload-linked neurodegenerative diseases.

Parga J.A., Rodriguez-Perez A.I., Garcia-Garrote M., Rodriguez-Pallares J., Labandeira-Garcia J.L.

Reactive oxygen species (ROS) are signalling molecules used to regulate cellular metabolism and homeostasis. However, excessive ROS production causes oxidative stress, one of the main mechanisms associated with the origin and progression of neurodegenerative disorders such as Parkinson’s disease. NRF2 (Nuclear Factor-Erythroid 2 Like 2) is a transcription factor that orchestrates the cellular response to oxidative stress. The regulation of NRF2 signalling has been shown to be a promising strategy to modulate the progression of the neurodegeneration associated to Parkinson’s disease. The NRF2 pathway has been shown to be affected in patients with this disease, and activation of NRF2 has neuroprotective effects in preclinical models, demonstrating the therapeutic potential of this pathway. In this review, we highlight recent advances regarding the regulation of NRF2, including the effect of Angiotensin II as an endogenous signalling molecule able to regulate ROS production and oxidative stress in dopaminergic neurons. The genes regulated and the downstream effects of activation, with special focus on Kruppel Like Factor 9 (KLF9) transcription factor, provide clues about the mechanisms involved in the neurodegenerative process as well as future therapeutic approaches.

Li X., Zou Y., Fu Y., Xing J., Wang K., Wan P., Zhai X.

Folic acid (FA)-induced acute kidney injury (AKI) is characterized by the disturbance of redox homeostasis, resulting in massive tubular necrosis and inflammation. Α-lipoic acid (LA), as an antioxidant, has been reported to play an important role in renal protection, but the underlying mechanism remains poorly explored. The aim of this study is to investigate the protective effect of LA on FA-induced renal damage. Our findings showed that LA could ameliorate renal dysfunction and histopathologic damage induced by FA overdose injection. Moreover, FA injection induced severe inflammation, indicated by increased release of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-1β, as well as infiltration of macrophage, which can be alleviated by LA supplementation. In addition, LA not only reduced the cellular iron overload by upregulating the expressions of Ferritin and ferroportin (FPN), but also mitigated reactive oxygen species (ROS) accumulation and lipid peroxidation by increasing the levels of antioxidant glutathione (GSH) and glutathione peroxidase-4 (GPX4). More importantly, we found that LA supplementation could reduce the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive tubular cells caused by FA, indicating that the tubular cell death mediated by ferroptosis may be inhibited. Further study demonstrated that LA supplementation could reverse the decreased expression of cystine/glutamate antiporter xCT (SLC7A11), which mediated GSH synthesis. What is more, mechanistic study indicated that p53 activation was involved in the inhibitory effect of SLC7A11 induced by FA administration, which could be suppressed by LA supplementation. Taken together, our findings indicated that LA played the protective effect on FA-induced renal damage mainly by inhibiting ferroptosis.

Su G., Yang W., Wang S., Geng C., Guan X.

Ferroptosis is a new form of programmed cell death characterized by an iron-dependent increase in lipid ROS. It has recently been reported that elevated iron levels in macrophages in plaques are associated with atherosclerosis(AS). However, it is not clear whether iron induces ferroptosis and the mechanism of ferroptosis induced by iron in macrophages in plaque. THP-1 macrophages were treated with ox-LDL and ferric ammonium citrate(FAC). Activate SIRT1 using SRT1720. Use of RAPA and CQ to promote and suppress autophagy. The expression of SIRT1, GPX4 was detected by Western Blot, and the cell activity and lipid ROS level were also performed. IL-1β and IL-18 levels were measured using qRT-PCR and ELISA. In this study, we determined that FAC can induce a decrease in foam cell activity rather than macrophage activity, increase lipid ROS levels, decrease GPX4 expression and inhibit SIRT1 expression, and increase IL-1β and IL-18 levels. SRT1720 activated SIRT1 and reversed the above changes induced by FAC. CQ partially prevents the above changes caused by activating SIRT1. Activation of SIRT1 can inhibit the ferroptosis and IL-1β and IL-18 levels of foam cells in excess iron by autophagy, providing a novel therapeutic target for AS. • Iron induced ferroptosis of foam cells, but not macrophage cells. • Iron-induced ferroptosis promoted the expression of IL-1β and IL-18. • Iron inhibited the expression of SIRT1 in foam cells. • Activated SIRT1 inhibited ferroptosis of foam cells. • SIRT1 reduces foam cell ferroptosis by restoring autophagy flux.

Biondetti E., Santin M.D., Valabrègue R., Mangone G., Gaurav R., Pyatigorskaya N., Hutchison M., Yahia-Cherif L., Villain N., Habert M., Arnulf I., Leu-Semenescu S., Dodet P., Vila M., Corvol J., et. al.

Abstract In Parkinson’s disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson’s disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson’s disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson’s disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson’s disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.

Tolosa E., Garrido A., Scholz S.W., Poewe W.

Parkinson's disease is the second most common neurodegenerative disease and its prevalence has been projected to double over the next 30 years. An accurate diagnosis of Parkinson's disease remains challenging and the characterisation of the earliest stages of the disease is ongoing. Recent developments over the past 5 years include the validation of clinical diagnostic criteria, the introduction and testing of research criteria for prodromal Parkinson's disease, and the identification of genetic subtypes and a growing number of genetic variants associated with risk of Parkinson's disease. Substantial progress has been made in the development of diagnostic biomarkers, and genetic and imaging tests are already part of routine protocols in clinical practice, while novel tissue and fluid markers are under investigation. Parkinson's disease is evolving from a clinical to a biomarker-supported diagnostic entity, for which earlier identification is possible, different subtypes with diverse prognosis are recognised, and novel disease-modifying treatments are in development.

Mahoney-Sánchez L., Bouchaoui H., Ayton S., Devos D., Duce J.A., Devedjian J.

Parkinson's Disease (PD) is a common and progressive neurodegenerative disorder characterised by motor impairments as well as non-motor symptoms. While dopamine-based therapies are effective in fighting the symptoms in the early stages of the disease, a lack of neuroprotective drugs means that the disease continues to progress. Along with the traditionally recognised pathological hallmarks of dopaminergic neuronal death and intracellular α-synuclein (α-syn) depositions, iron accumulation, elevated oxidative stress and lipid peroxidation damage are further conspicuous features of PD pathophysiology. However, the underlying mechanisms linking these pathological hallmarks with neurodegeneration still remain unclear. Ferroptosis, a regulated iron dependent cell death pathway involving a lethal accumulation of lipid peroxides, shares several features with PD pathophysiology. Interestingly, α-syn has been functionally linked with the metabolism of both iron and lipid, suggesting a possible interplay between dysregulated α-syn and other PD pathological hallmarks related to ferroptosis. This review will address the importance for understanding these disease mechanisms that could be targeted therapeutically. Anti-ferroptosis molecules are neuroprotective in PD animal models and the anti-ferroptotic iron chelator, deferiprone, slowed disease progression and improved motor function in two independent clinical trials for PD. An ongoing larger multi-centre phase 2 clinical trial will confirm the therapeutic potential of deferiprone and the relevance of ferroptosis in PD. This review addresses the known pathological features of PD in relation to the ferroptosis pathway with therapeutic implications of targeting this cell death pathway.

Wu Y., Truong D., Wang X., Feng Y., Li X.

Chen X., Yu C., Kang R., Tang D.

Ferroptosis is a form of regulated cell death that is characterized by iron-dependent oxidative damage and subsequent plasma membrane ruptures and the release of damage-associated molecular patterns. Due to the role of iron in mediating the production of reactive oxygen species and enzyme activity in lipid peroxidation, ferroptosis is strictly controlled by regulators involved in many aspects of iron metabolism, such as iron uptake, storage, utilization, and efflux. Translational and transcriptional regulation of iron homeostasis provide an integrated network to determine the sensitivity of ferroptosis. Impaired ferroptosis is implicated in various iron-related pathological conditions or diseases, such as cancer, neurodegenerative diseases, and ischemia-reperfusion injury. Understanding the molecular mechanisms underlying the regulation of iron metabolism during ferroptosis may provide effective strategies for the treatment of ferroptosis-associated diseases. Indeed, iron chelators effectively prevent the occurrence of ferroptosis, which may provide new approaches for the treatment of iron-related disorders. In this review, we summarize recent advances in the theoretical modeling of iron-dependent ferroptosis, and highlight the therapeutic implications of iron chelators in diseases.

Chen X., Li J., Kang R., Klionsky D.J., Tang D.

Tai S., Zheng Q., Zhai S., Cai T., Xu L., Yang L., Jiao L., Zhang C.

Disruption of neuronal iron homeostasis and oxidative stress are related to the pathogenesis of Parkinson’s disease (PD). Alpha-lipoic acid (ALA), a naturally occurring enzyme cofactor with antioxidant and iron chelator properties, has many known effects. It is known that ALA has neuroprotective effects on PD, but its underlying mechanism remains unclear. In the present study, we established PD models induced by 6-hydroxydopamine (6-OHDA) to explore the neuroprotective ability of ALA and its underlying mechanism in vivo and in vitro. Our results showed that ALA could provide significant protection from 6-OHDA-induced cell damage in vitro by decreasing the levels of intracellular reactive oxygen species and iron. Moreover, ALA significantly promoted the survival of the dopaminergic neuron in the 6-OHDA-induced PD rat model and remarkably ameliorates motor deficits by dramatically inhibiting the decrease of tyrosine hydroxylase expression and superoxide dismutase activity in the substantia nigra (SN). Interestingly, ALA attenuated 6-OHDA-induced iron accumulation both in the vivo and vitro by antagonizing 6-OHDA-induced up-regulation of iron regulatory protein 2 (IRP2) and divalent metal transporter 1 (DMT1). These results indicate that the neuroprotective mechanism of ALA against neurological injury induced by 6-OHDA may be related to the regulation of iron homeostasis and the reduced oxidative stress levels. Therefore, ALA may provide neuroprotective therapy for PD and other iron metabolism disorder related diseases.

Zhang T., Zhang Y., Xie J., Lu D., Wang L., Zhao S., Zhou J., Cheng Y., Kou T., Wang J., Chen Y., Xu L., Hu X., Ying Y., Wang J., et. al.

Ferroptosis, a non-apoptotic, iron-dependent form of regulated cell death, is closely related to the pathogenesis of neurodegenerative diseases. Stem cells and their derivatives exhibit remarkable potential in modulating ferroptosis, offering promising therapeutic intervention for neurodegenerative diseases. In this review, we systematically explore neurological aging and its association with cognitive impairment and neurodegenerative diseases, with focus on the molecular mechanisms of ferroptosis in neurodegenerative diseases and the potential therapeutic strategies of stem cell derivatives for neurological diseases.

Zhang Y., Kong F., Li N., Tao L., Zhai J., Ma J., Zhang S.

Ferroptosis is a novel form of cell death that uniquely requires iron and is characterized by iron accumulation, the generation of free radicals leading to oxidative stress, and the formation of lipid peroxides, which distinguish it from other forms of cell death. The regulation of ferroptosis is extremely complex and is closely associated with a spectrum of diseases. Sirtuin 1 (SIRT1), a NAD + -dependent histone deacetylase, has emerged as a pivotal epigenetic regulator with the potential to regulate ferroptosis through a wide array of genes intricately associated with lipid metabolism, iron homeostasis, glutathione biosynthesis, and redox homeostasis. This review provides a comprehensive overview of the specific mechanisms by which SIRT1 regulates ferroptosis and explores its potential therapeutic value in the context of multiple disease pathologies, highlighting the significance of SIRT1-mediated ferroptosis in treatment strategies.

Liu C., Pan J., Bao Q.

Ni R., Jiang J., Wang F., Min J.

Both iron metabolism and ferroptosis (an iron-dependent form of programmed cell death) have been connected to the development and progression of many currently incurable non-communicable diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease, metabolic dysfunction-associated steatohepatitis, heart failure, and both treatment-relapsed and refractory cancers, such as pancreatic ductal adenocarcinoma and triple-negative breast cancer. Thus, understanding the relationship between iron and these diseases can pave the way for the development of novel therapeutic strategies. Here, we summarize the latest evidence supporting the pathological roles of dysregulated iron metabolism and ferroptosis in a wide range of preclinical animal models of these currently incurable non-communicable diseases. We also summarize the feasibility of targeting iron metabolism and ferroptosis for the prevention and treatment of iron- and ferroptosis-related diseases that currently have limited treatment options. In addition, we provide our perspectives on the challenges and promises regarding the translational potential of targeting dysregulated iron metabolism and ferroptosis to treat diseases, highlighting the future roadmap for developing iron- and ferroptosis-targeted therapeutics.

Jiao D., Yang Y., Wang K., Wang Y.

Parkinson disease (PD) is the second most common neurodegenerative disease, and its incidence is climbing every year, but there is still a lack of effective clinical treatments. In recent years, many studies have shown that ferroptosis plays a key role in the progression of PD. Most importantly, many cellular and animal studies and clinical trials have shown that episodes of PD can be alleviated by inhibiting the ferroptosis process, such as utilizing inhibitors, chelating agents, and others. Here, we review the role of ferroptosis, a new form of cell death, in the pathogenesis of PD, and summarize the therapeutic strategies for targeting ferroptosis in PD, hoping to provide new thinking for the study of PD pathogenesis and the development of therapeutic strategies.

Liu H., Li M., Deng Y., Hou Y., Hou L., Zhang X., Zheng Z., Guo F., Sun K.

Iron homeostasis is critical for multiple physiological and pathological processes. DMT1, a core iron transporter, is expressed in almost all cells and organs and altered in response to various conditions, whereas, there is few reviews focusing on DMT1 in diseases associated with aberrant iron metabolism. Based on available knowledge, this review described a full view of DMT1 and summarized the roles of DMT1 and DMT1-mediated iron metabolism in the onset and development of inflammatory and degenerative diseases. This review also provided an overview of DMT1-related treatment in these disorders, highlighting its therapeutic potential in chronic inflammatory and degenerative diseases.

Shanaida M., Lysiuk R., Mykhailenko O., Hudz N., Abdulsalam A., Gontova T., Oleshchuk O., Ivankiv Y., Shanaida V., Lytkin D., Bjørklund G.

Abstract: The anti-aging effects of alpha-lipoic acid (αLA), a natural antioxidant synthesized in human tissues, have attracted a growing interest in recent years. αLA is a short- -chain sulfur-containing fatty acid occurring in the mitochondria of all kinds of eukaryotic cells. Both the oxidized disulfide of αLA and its reduced form (dihydrolipoic acid, DHLA) exhibit prominent antioxidant function. The amount of αLA inside the human body gradually decreases with age resulting in various health disorders. Its lack can be compensated by supplying from external sources such as dietary supplements or medicinal dosage forms. The primary objectives of this study were the analysis of updated information on the latest two-decade research regarding the use of αLA from an anti-aging perspective. The information was collected from PubMed, Wiley Online Library, Scopus, ScienceDirect, SpringerLink, Google Scholar, and clinicaltrials.gov. Numerous in silico, in vitro, in vivo, and clinical studies revealed that αLA shows a protective role in biological systems by direct or indirect reactive oxygen/nitrogen species quenching. αLA demonstrated beneficial properties in the prevention and treatment of many age-related disorders such as neurodegeneration, metabolic disorders, different cancers, nephropathy, infertility, and skin senescence. Its preventive effects in case of Alzheimer's and Parkinson's diseases are of particular interest. Further mechanistic and clinical studies are highly recommended to evaluate the wide spectrum of αLA therapeutic potential that could optimize its dietary intake for prevention and alleviation disorders related to aging.

Xu M., Li T., Liu X., Islam B., Xiang Y., Zou X., Wang J.

Mitochondrial dysfunction is well recognized as a critical component of the complicated pathogenesis of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. This review investigates the influence of mitochondrial DNA single nucleotide polymorphisms on mitochondrial function, as well as their role in the onset and progression of these neurodegenerative diseases. Furthermore, the contemporary approaches to mitochondrial regulation in these disorders are discussed. Our objective is to uncover early diagnostic targets and formulate precision medicine strategies for neurodegenerative diseases, thereby offering new paths for preventing and treating these conditions.

Wang Y., Li D., Xu K., Wang G., Zhang F.

Copper, one of the most prolific transition metals in the body, required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine (DPA), and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline (PBT2), along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.

Pal C.

Parkinson's disease (PD), a neurodegenerative disorder, is one of the most significant challenges confronting modern societies, affecting millions of patients globally each year. The pathophysiology of PD is significantly influenced by mitochondrial dysfunction, as evident by the contribution of altered mitochondrial dynamics, bioenergetics, and increased oxidative stress to neuronal death. This review examines the potential use of small molecules that target mitochondria as a therapeutic approach for treating PD. Progress in mitochondrial biology has revealed various mitochondrial targets that can be modulated to restore function and mitigate neurodegeneration. Small molecules that promote mitochondrial biogenesis, enhance mitochondrial dynamics, decrease oxidative stress, and prevent the opening of the mitochondrial permeability transition pore (mPTP) have shown promise in preclinical models. Additionally, targeting mitochondrial quality control mechanisms, such as mitophagy, provides another therapeutic approach. This review explores recent research on small molecules targeting mitochondria, examines their mechanisms of action, and assesses their potential efficacy and safety profiles. By highlighting the most promising candidates and addressing the challenges and future directions in this field, this review aims to offer a comprehensive overview of current and future prospects for mitochondrial-targeted therapies in PD. Ultimately, treating mitochondrial dysfunction holds significant promise for developing disease-modifying PD medications, giving patients hope for better outcomes and improved quality of life.

Salis Torres A., Lee J., Caporali A., Semple R.K., Horrocks M.H., MacRae V.E.

Individuals diagnosed with Parkinson’s disease (PD) often exhibit heightened susceptibility to cardiac dysfunction, reflecting a complex interaction between these conditions. The involvement of mitochondrial dysfunction in the development and progression of cardiac dysfunction and PD suggests a plausible commonality in some aspects of their molecular pathogenesis, potentially contributing to the prevalence of cardiac issues in PD. Mitochondria, crucial organelles responsible for energy production and cellular regulation, play important roles in tissues with high energetic demands, such as neurons and cardiac cells. Mitochondrial dysfunction can occur in different and non-mutually exclusive ways; however, some mechanisms include alterations in mitochondrial dynamics, compromised bioenergetics, biogenesis deficits, oxidative stress, impaired mitophagy, and disrupted calcium balance. It is plausible that these factors contribute to the increased prevalence of cardiac dysfunction in PD, suggesting mitochondrial health as a potential target for therapeutic intervention. This review provides an overview of the physiological mechanisms underlying mitochondrial quality control systems. It summarises the diverse roles of mitochondria in brain and heart function, highlighting shared pathways potentially exhibiting dysfunction and driving cardiac comorbidities in PD. By highlighting strategies to mitigate dysfunction associated with mitochondrial impairment in cardiac and neural tissues, our review aims to provide new perspectives on therapeutic approaches.

Zhu L., Yang M., Fan L., Yan Q., Zhang L., Mu P., Lu F.

Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, pose significant health challenges and economic burdens worldwide. Recent studies have emphasized the potential therapeutic value of activating silent information regulator-1 (SIRT1) in treating these conditions. Resveratrol, a compound known for its ability to potently activate SIRT1, has demonstrated promising neuroprotective effects by targeting the underlying mechanisms of neurodegeneration. In this review, we delve into the crucial role of resveratrol-mediated SIRT1 upregulation in improving neurodegenerative diseases. The role of the activation of SIRT1 by resveratrol was reviewed. Moreover, network pharmacology was used to elucidate the possible mechanisms of resveratrol in these diseases. Activation of SIRT1 by resveratrol had positive effects on neuronal function and survival and alleviated the hallmark features of these diseases, such as protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. In terms of network pharmacology, the signaling pathways by which resveratrol protects against different neurodegenerative diseases were slightly different. Although the precise mechanisms underlying the neuroprotective effects of resveratrol and SIRT1 activation remain under investigation, these findings offer valuable insights into potential therapeutic strategies for neurodegenerative diseases.

Su Y., Jiao Y., Cai S., Xu Y., Wang Q., Chen X.

Neurodegenerative diseases such as Parkinson's disease (PD) have complex pathogenetic mechanisms. Genetic, age, and environmental factors are all related to PD. Due to the unclear pathogenesis of PD and the lack of effective cure methods, it is urgent to find new targets for treating PD patients. Ferroptosis is a form of cell death that is reliant on iron and exhibits distinct morphological and mechanistic characteristics compared to other types of cell death. It encompasses a range of biological processes, including iron/lipid metabolism and oxidative stress. In recent years, research has found that ferroptosis plays a crucial role in the pathophysiological processes of neurodegenerative diseases and stroke. Therefore, ferroptosis is also closely related to PD, This article reviews the core mechanisms of ferroptosis and elucidates the correlation between PD and ferroptosis. In addition, new compounds that have emerged in recent years to exert anti PD effects by inhibiting the ferroptosis signaling pathway were summarized. I hope to further elaborate the relationship between ferroptosis and PD through the review of this article, and provide new strategies for developing PD treatments targeting ferroptosis.

Abdolmaleki A., Karimian A., Khoshnazar S.M., Asadi A., Samarein Z.A., Smail S.W., Bhattacharya D.

Abstract The protein, Nuclear factor-E2-related factor 2 (Nrf2), is a transitory protein that acts as a transcription factor and is involved in the regulation of many cytoprotective genes linked to xenobiotic metabolism and antioxidant responses. Based on the existing clinical and experimental data, it can be inferred that neurodegenerative diseases are characterized by an excessive presence of markers of oxidative stress (OS) and a reduced presence of antioxidant defense systems in both the brain and peripheral tissues. The presence of imbalances in the homeostasis between oxidants and antioxidants has been recognized as a substantial factor in the pathogenesis of neurodegenerative disorders. The dysregulations include several cellular processes such as mitochondrial failure, protein misfolding, and neuroinflammation. These dysregulations all contribute to the disruption of proteostasis in neuronal cells, leading to their eventual mortality. A noteworthy component of Nrf2, as shown by recent research undertaken over the last decade, is to its role in the development of resistance to OS. Nrf2 plays a pivotal role in regulating systems that defend against OS. Extant research offers substantiation for the protective and defensive roles of Nrf2 in the context of neurodegenerative diseases. The purpose of this study is to provide a comprehensive analysis of the influence of Nrf2 on OS and its function in regulating antioxidant defense systems within the realm of neurodegenerative diseases. Furthermore, we evaluate the most recent academic inquiries and empirical evidence about the beneficial and potential role of certain Nrf2 activator compounds within the realm of therapeutic interventions.

Lv Q., Tao K., Yao X., Pang M., Cao B., Liu C., Wang F.

AbstractParkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons and aggregation of α‐synuclein (α‐syn). Ferroptosis, a form of cell death induced by iron accumulation and lipid peroxidation, is involved in the pathogenesis of PD. It is unknown whether melatonin receptor 1 (MT1) modulates α‐syn and ferroptosis in PD. Here, we used α‐syn preformed fibrils (PFFs) to induce PD models in vivo and in vitro. In PD mice, α‐syn aggregation led to increased iron deposition and ferroptosis. MT1 knockout exacerbated these changes and resulted in more DA neuronal loss and severe motor impairment. MT1 knockout also suppressed the Sirt1/Nrf2/Ho1/Gpx4 pathway, reducing resistance to ferroptosis, and inhibited expression of ferritin Fth1, leading to more release of ferrous ions. In vitro experiments confirmed these findings. Knockdown of MT1 enhanced α‐syn PFF‐induced intracellular α‐syn aggregation and suppressed expression of the Sirt1/Nrf2/Ho1/Gpx4 pathway and Fth1 protein, thereby aggravating ferroptosis. Conversely, overexpression of MT1 reversed these effects. Our findings reveal a novel mechanism by which MT1 activation prevents α‐syn‐induced ferroptosis in PD, highlighting the neuroprotective role of MT1 in PD.