Dopaminergic Cell Death Research Articles

Alpha-synuclein preformed fibril-induced aggregation and dopaminergic cell death in cathepsin D overexpression and ZKSCAN3 knockout mice.

α-synuclein accumulation is recognized as a prominent feature in the majority of Parkinson's disease cases and also occurs in a broad range of neurodegenerative disorders including Alzheimer's disease. It has been shown that α-synuclein can spread from a donor cell to neighboring cells and thus propagate cellular damage, antagonizing the effectiveness of therapies such as transplantation of fetal or iPSC derived dopaminergic cells. As we and others previously have shown, insufficient lysosomal function due to genetic mutations or targeted disruption of cathepsin D can cause α-synuclein accumulation. We here investigated whether overexpression of cathepsin D or knockout (KO) of the transcriptional suppressor of lysosomal biogenesis ZKSCAN3 can attenuate propagation of α-synuclein aggregation and cell death. We examined dopaminergic neurodegeneration in the substantia nigra using stereology of tyrosine hydroxylase-immunoreactive cells 4 months and 6 months after intrastriatal injection of α-synuclein preformed fibrils or monomeric α-synuclein control in control, central nervous system (CNS)-cathepsin D overexpressing and CNS-specific ZKSCAN3 KO mice. We also examined pS129-α-synuclein aggregates in the substantia nigra, cortex, amygdala and striatum. The extent of dopaminergic neurodegeneration and pS129-α-synuclein aggregation in the brains of CNS-specific ZKSCAN3 knockout mice and CNS-cathepsin D overexpressing mice was similar to that observed in wild-type mice. Our results indicate that neither enhancing cathepsin D expression nor disrupting ZKSCAN3 in the CNS is sufficient to attenuate pS129-α-synuclein aggregate accumulation or dopaminergic neurodegeneration.

Associations between neuromelanin depletion and cortical rhythmic activity in Parkinson's disease.

Parkinson's disease (PD) is marked by the death of neuromelanin-rich dopaminergic and noradrenergic cells in the substantia nigra (SN) and the locus coeruleus (LC), respectively, resulting in motor and cognitive impairments. While SN dopamine dysfunction has clear neurophysiological effects, the association of reduced LC norepinephrine signaling with brain activity in PD remains to be established. We used neuromelanin-sensitive T1-weighted MRI (NPD = 58; NHC = 27) and task-free magnetoencephalography (NPD = 58; NHC = 65) to identify neuropathophysiological factors related to the degeneration of the LC and SN in patients with PD. We found pathological increases in rhythmic alpha (8-12 Hz) activity in patients with decreased LC neuromelanin, with a stronger association in patients with worse attentional impairments. This negative alpha-LC neuromelanin relationship is strongest in fronto-motor cortices, where alpha activity is inversely related to attention scores. Using neurochemical colocalization analyses with normative atlases of neurotransmitter transporters, we also show that this effect is more pronounced in regions with high densities of norepinephrine transporters. These observations support a noradrenergic association between LC integrity and alpha band activity. Our data also show that rhythmic beta (15-29 Hz) activity in the left somato-motor cortex decreases with lower levels of SN neuromelanin; the same regions where beta activity reflects axial motor symptoms. Together, our findings clarify the association of well-documented alterations of rhythmic neurophysiology in PD with cortical and subcortical neurochemical systems. Specifically, attention-related alpha activity is related to dysfunction of the noradrenergic system, and beta activity with relevance to motor impairments reflects dopaminergic dysfunction.

A Model with Dopamine Depletion in Basal Ganglia and Cerebellum Predicts Changes in Thalamocortical Beta Oscillations.

Parkinsonism is presented as a motor syndrome characterized by rigidity, tremors, and bradykinesia, with Parkinson's disease (PD) being the predominant cause. The discovery that those motor symptoms result from the death of dopaminergic cells in the substantia nigra led to focus most of parkinsonism research on the basal ganglia (BG). However, recent findings point to an active involvement of the cerebellum in this motor syndrome. Here, we have developed a multiscale computational model of the rodent brain's BG-cerebellar network. Simulations showed that a direct effect of dopamine depletion on the cerebellum must be taken into account to reproduce the alterations of neural activity in parkinsonism, particularly the increased beta oscillations widely reported in PD patients. Moreover, dopamine depletion indirectly impacted spike-time-dependent plasticity at the parallel fiber-Purkinje cell synapses, degrading associative motor learning as observed in parkinsonism. Overall, these results suggest a relevant involvement of cerebellum in parkinsonism associative motor symptoms.

Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson’s disease models

BackgroundClinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival.MethodsIn a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection.ResultsAt the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats.ConclusionsThe results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.

Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling.

Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. Receptor interacting protein kinase-3 (RIPK3) signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine model of Parkinson's disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of damage-associated molecular pattern signaling. In mechanistic experiments, we showed that factors released from dying neurons signaled through receptor for advanced glycation endproducts to induce astrocytic RIPK3 signaling, which conferred inflammatory and neurotoxic functional activity. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3.

Targeting phosphodiesterase 4 as a potential therapy for Parkinson's disease: a review.

Phosphodiesterases (PDEs) have become a promising therapeutic target for various disorders. PDEs are a vast and diversified family of enzymes that degrade cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which have several biochemical and physiological functions. Phosphodiesterase 4 (PDE4) is the most abundant PDE in the central nervous system (CNS) and is extensively expressed in the mammalian brain, where it catalyzes the hydrolysis of intracellular cAMP. An alteration in the balance of PDE4 and cAMP results in the dysregulation of different biological mechanisms involved in neurodegenerative diseases. By inhibiting PDE4 with drugs, the levels of cAMP inside the cells could be stabilized, which may improve the symptoms of mental and neurological disorders such as memory loss, depression, and Parkinson's disease (PD). Though numerous studies have shown that phosphodiesterase 4 inhibitors (PDE4Is) are beneficial in PD, there are presently no approved PDE4I drugs for PD. This review presents an overview of PDE4Is and their effects on PD, their possible underlying mechanism in the restoration/protection of dopaminergic cell death, which holds promise for developing PDE4Is as a treatment strategy for PD. Methods on how these drugs could be effectively delivered to develop as a promising treatment for PD have been suggested.

Nr1h4 and Thrb ameliorate ER stress and provide protection in the MPTP mouse model of Parkinson's.

Elevated ER stress has been linked to the pathogenesis of several disease conditions including neurodegeneration. In this study, we have holistically determined the differential expression of all the nuclear receptors (NRs) in the presence of classical ER stress inducers. Activation of Nr1h4 and Thrb by their cognate ligands (GW4064 and T3) ameliorates the tunicamycin (TM)-induced expression of ER stress genes. A combination of both ligands is effective in mitigating cell death induced by TM. Further exploration of their protective effects in the Parkinson's disease (PD) model shows that they reduce MPP+-induced dissipation of mitochondrial membrane potential and ROS generation in an in vitro PD model in neuronal cells. Furthermore, the generation of an experimental murine PD model reveals that simultaneous treatment of GW4064 and T3 protects mice from ER stress, dopaminergic cell death, and functional deficits in the MPTP mouse model of PD. Thus, activation of Nr1h4 and Thrb by their respective ligands plays an indispensable role in ER stress amelioration and mounts protective effects in the MPTP mouse model of PD.

Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.

Parkinson's disease (PD) is a progressive neurogenerative movement disorder characterized by dopaminergic cell death within the substantia nigra pars compacta (SNpc) due to the aggregation-prone protein α-synuclein. Accumulation of α-synuclein is implicated in mitochondrial dysfunction and disruption of the autophagic turnover of mitochondria, or mitophagy, which is an essential quality control mechanism proposed to preserve mitochondrial fidelity in response to aging and stress. Yet, the precise relationship between α-synuclein accumulation, mitochondrial autophagy, and dopaminergic cell loss remains unresolved. Here, we determine the kinetics of α-synuclein overexpression and mitophagy using the pH-sensitive fluorescent mito-QC reporter. We find that overexpression of mutant A53T α-synuclein in either human SH-SY5Y cells or rat primary cortical neurons induces mitophagy. Moreover, the accumulation of mutant A53T α-synuclein in the SNpc of rats results in mitophagy dysregulation that precedes the onset of dopaminergic neurodegeneration. This study reveals a role for mutant A53T α-synuclein in inducing mitochondrial dysfunction, which may be an early event contributing to neurodegeneration.

The lysosomal β-glucocerebrosidase strikes mitochondria: implications for Parkinson's therapeutics.

Parkinson's disease is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in the substantia nigra. However, the precise molecular aetiology of the disease is still unclear. Several cellular pathways have been linked to Parkinson's disease, including the autophagy-lysosome pathway, α-synuclein aggregation and mitochondrial function. Interestingly, the mechanistic link between GBA1, the gene that encodes for lysosomal β-glucocerebrosidase (GCase), and Parkinson's disease lies in the interplay between GCase functions in the lysosome and mitochondria. GCase mutations alter mitochondria-lysosome contact sites. In the lysosome, reduced GCase activity leads to glycosphingolipid build-up, disrupting lysosomal function and autophagy, thereby triggering α-synuclein accumulation. Additionally, α-synuclein aggregates reduce GCase activity, creating a self-perpetuating cycle of lysosomal dysfunction and α-synuclein accumulation. GCase can also be imported into the mitochondria, where it promotes the integrity and function of mitochondrial complex I. Thus, GCase mutations that impair its normal function increase oxidative stress in mitochondria, the compartment where dopamine is oxidized. In turn, the accumulation of oxidized dopamine adducts further impairs GCase activity, creating a second cycle of GCase dysfunction. The oxidative state triggered by GCase dysfunction can also induce mitochondrial DNA damage which, in turn, can cause dopaminergic cell death. In this review, we highlight the pivotal role of GCase in Parkinson's disease pathogenesis and discuss promising examples of GCase-based therapeutics, such as gene and enzyme replacement therapies, small molecule chaperones and substrate reduction therapies, among others, as potential therapeutic interventions.

Rat Pharmacokinetics and In Vitro Metabolite Identification of KM-819, a Parkinson's Disease Candidate, Using LC-MS/MS and LC-HRMS.

FAF1 (FAS-associated factor 1) is involved in the activation of Fas cell surface death receptors and plays a role in apoptosis and necrosis. In patients with Parkinson's disease, FAF1 is overexpressed in dopaminergic neurons in the substantia nigra. KM-819, an FAF1 inhibitor, has shown potential for preventing dopaminergic neuronal cell death, promoting the degradation of α-synuclein and preventing its accumulation. This study aimed to develop and validate a quantitative analytical method for determining KM-819 levels in rat plasma using liquid chromatography-tandem mass spectrometry. This method was then applied to pharmacokinetic (PK) studies in rats. The metabolic stability of KM-819 was assessed in rat, dog, and human hepatocytes. In vitro metabolite identification and metabolic pathways were investigated in rat, dog, and human hepatocytes. The structural analog of KM-819, namely N-[1-(4-bromobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(phenylsulfanyl) acetamide, served as the internal standard (IS). Proteins were precipitated from plasma samples using acetonitrile. Analysis was carried out using a reverse-phase C18 column with a mobile phase consisting of 0.1% formic acid in distilled water and 0.1% formic acid in acetonitrile. The analytical method developed for KM-819 exhibited linearity within the concentration range of 0.002-10 μg/mL in rat plasma. The precision and accuracy of the intra- and inter-day measurements were <15% for the lower limit of quantification (LLOQ) and all quality control samples. KM-819 demonstrated stability under various sample storage conditions (6 h at room temperature (25 °C), four weeks at -20 °C, three freeze-thaw cycles, and pretreated samples in the autosampler). The matrix effect and dilution integrity met the criteria set by the Food and Drug Administration and the European Medicines Agency. This sensitive, rapid, and reliable analytical method was successfully applied in pharmacokinetic studies in rats. Pharmacokinetic analysis revealed the dose-independent kinetics of KM-819 at 0.5-5 mg/kg, with a moderate oral bioavailability of ~20% in rats. The metabolic stability of KM-819 was also found to be moderate in rat, dog, and human hepatocytes. Metabolite identification in rat, dog, and human hepatocytes resulted in the discovery of six, six, and eight metabolites, respectively. Glucuronidation and mono-oxidation have been proposed as the major metabolic pathways. Overall, these findings contribute to a better understanding of the pharmacokinetic characteristics of KM-819, thereby aiding future clinical studies.

Alleviating Stress in Parkinson's Disease: Symptomatic Treatment, Disease Modification, or Both?

Psychological stress, a state of mental strain caused by mentally or physically threatening situations, plays a significant role in Parkinson's disease (PD). Motor symptoms worsen during acute stress and common non-motor symptoms in PD, such as anxiety and depression, are linked to chronic stress. Although evidence in humans is lacking, animal models of PD suggest that chronic stress can accelerate dopaminergic cell death. This suggests that stress-reducing interventions have not only symptomatic, but perhaps also disease-modifying effects. Our objective was to identify the most promising strategies for stress-reduction in PD and to analyze their potential value for disease-modification. An unstructured literature search was performed, primarily focusing on papers published between 2020-2023. Several large clinical trials have tested the efficacy of aerobic exercise and mindfulness-based interventions on PD symptoms. The evidence is promising, but not definitive yet: some exercise trials found a reduction in stress-related symptoms, whereas others did not or did not report it. In the majority of trials, biological measures of stress and of disease progression are missing. Furthermore, follow-up periods were generally too short to measure disease-modifying effects. Hence, mechanisms underlying the intervention effects remain largely unclear. These effects may consist of attenuating progressive neurodegeneration (measured with MRI-markers of substantia nigra integrity or cortical thickness), or a strengthening of compensatory cerebral mechanisms (measured with functional neuroimaging), or both. Lifestyle interventions are effective for alleviating stress-related symptoms in PD. They hold potential for exerting disease-modifying effects, but new evidence in humans is necessary to fulfill that promise.

Amelioration of Motor Performance and Nigrostriatal Dopamine Cell Volume Using a Novel Far-Infrared Ceramic Blanket in an A53T Alpha-Synuclein Transgenic Parkinson's Disease Mouse Model.

We had attended a Parkinson's Disease (PD) patient for a non-healing wound who reported a marked decrease in his hand tremor and freezing of gait when his wound was exposed to a ceramic far-field infrared (cFIR) blanket. PD is the most frequent motor disorder and the second most frequent neurodegenerative disease after Alzheimer's Disease (AD). The tremor, rigidity, and slowness of movement associated with Parkinson's disease (PD) affect up to 10 million people throughout the world, and the major contributing factor to the pathogenesis of PD is the accumulation and propagation of pathological α-synuclein (α-Syn) and the death of dopaminergic cells in the Nigrostriatal system. Efforts to slow or stop its spreading have resulted in the development and use of dopaminergic drug replacement therapy. Unfortunately, there is a loss of about 70-80% of substantia nigral dopaminergic neurons in patients by the time they are diagnosed with PD, and various dopaminergic drugs provide only temporary relief of their motor symptoms. There are limitations in treating PD with many conventional medications, necessitating a combination of pharmaceutical and non-pharmacological therapy as an essential adjunct to better address the health and welfare of PD patients. We used male adult A53T alpha-synuclein transgenic mice exposed to a ceramic far-infrared blanket. Motor activity was assessed using the rotarod apparatus, and mouse brains were examined to quantify the fluorescence intensities of the immunostained samples. A53T alpha-synuclein transgenic mice had a significantly shorter time stay on the rotating bar than the wild-type mice (B6C3H). The rotarod performance was significantly improved in A53T alpha-synuclein transgenic mice exposed to cFIR as well as B6C3H healthy wild mice exposed to cFIR. There was a significant statistical and substantive increase in the cellular composition of the Striatum and substantia nigra of cFIR-treated mice. Improvement in motor performance is seen in PD mice and wild mice and is associated with increases in cell volume in the substantia nigra and striatum after treatment.

Astrocytic Nrf2 Mediates the Neuroprotective and Anti-Inflammatory Effects of Nootkatone in an MPTP-Induced Parkinson's Disease Mouse Model.

This study aims to investigate the neuroprotective effects of nootkatone (NKT), a sesquiterpenoid compound isolated from grapefruit, in an MPTP-induced Parkinson's disease (PD) mouse model. NKT restored MPTP-induced motor impairment and dopaminergic neuronal loss and increased the expression of neurotrophic factors like BDNF, GDNF, and PGC-1α. In addition, NKT inhibited microglial and astrocyte activation and the expression of pro-inflammatory markers like iNOS, TNF-α, and IL-1β and oxidative stress markers like 4-HNE and 8-OHdG. NKT increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2)-driven antioxidant enzymes like HO-1 and NQO-1 in astrocytes, but not in neurons or microglia in MPTP-treated mice. To investigate whether Nrf2 mediates the anti-inflammatory, antioxidant, or neuroprotective effects of NKT, mice were pretreated with Nrf2-specific inhibitor brusatol (BT) prior to NKT treatment. BT attenuated the NKT-mediated inhibition of 4-HNE and 8-OHdG and the number of Nrf2+/HO-1+/NQO1+ cells co-localized with GFAP+ astrocytes in the substantia nigra of MPTP-treated mice. In addition, BT reversed the effects of NKT on dopaminergic neuronal cell death, neurotrophic factors, and pro-/anti-inflammatory cytokines in MPTP-treated mice. Collectively, these data suggest that astrocytic Nrf2 and its downstream antioxidant molecules play pivotal roles in mediating the neuroprotective and anti-inflammatory effects of NKT in an MPTP-induced PD mouse model.

Pathological Correlates of Cognitive Decline in Parkinson's Disease: From Molecules to Neural Networks.

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the death of dopaminergic neurons in the substantia nigra and appearance of protein aggregates (Lewy bodies) consisting predominantly of α-synuclein in neurons. PD is currently recognized as a multisystem disorder characterized by severe motor impairments and various non-motor symptoms. Cognitive decline is one of the most common and worrisome non-motor symptoms. Moderate cognitive impairments (CI) are diagnosed already at the early stages of PD, usually transform into dementia. The main types of CI in PD include executive dysfunction, attention and memory decline, visuospatial impairments, and verbal deficits. According to the published data, the following mechanisms play an essential role demonstrates a crucial importance in the decline of the motor and cognitive functions in PD: (1) changes in the conformational structure of transsynaptic proteins and protein aggregation in presynapses; (2) synaptic transmission impairment; (3) neuroinflammation (pathological activation of the neuroglia); (4) mitochondrial dysfunction and oxidative stress; (5) metabolic disorders (hypometabolism of glucose, dysfunction of glycolipid metabolism; and (6) functional rearrangement of neuronal networks. These changes can lead to the death of dopaminergic cells in the substantia nigra and affect the functioning of other neurotransmitter systems, thus disturbing neuronal networks involved in the transmission of information related to the regulation of motor activity and cognitive functions. Identification of factors causing detrimental changes in PD and methods for their elimination will help in the development of new approaches to the therapy of PD. The goal of this review was to analyze pathological processes that take place in the brain and underlie the onset of cognitive disorders in PD, as well as to describe the impairments of cognitive functions in this disease.

Parkinson Disease: A Review

Parkinson disease is a neurodegenerative progressive disorder which caused due to increase level of Ach and lack of dopamine inside the brain. The dopaminergic cell death were found inside the brain in case of Parkinson disease. It’s a type of motor deficiency disease. Many symptoms like bradykinesia, tremor, postural instability, loss of sense of smell etc. are arises in Parkinson disease and there is no specific cure for Parkinson. A molecular biomarker is important to find because it differentiate the Parkinson from other disease and this disease mainly consultant by the neurologist. The management and treatment of Parkinson disease is based on some drugs, like levodopa, dopamine agonist, MAO-beta inhibitor, CoMT inhibitors and many more. They are used with or without in combination and Parkinson include various risk factor like herbicides, pesticides, metal exposure etc. Various type of surgical approaches. Deep brain stimulation are good for Parkinson patients. Nicotine, caffeine, hormone replacement therapy are the some protective factors which overcome the chances of Parkinson disease.&#x0D;

Dopaminergic cell protection and alleviation of neuropsychiatric disease symptoms by VMAT2 expression through the class I HDAC inhibitor TC-H 106.

The importance of vesicular monoamine transporter 2 (VMAT2) in dopamine regulation, which is considered crucial for neuropsychiatric disorders, is currently being studied. Moreover, the development of disease treatments using histone deacetylase (HDAC) inhibitors (HDACi) is actively progressing in various fields. Recently, research on the possibility of regulating neuropsychiatric disorders has been conducted. In this study, we evaluated whether VMAT2 expression increased by an HDACi can fine-tune neuropsychotic behavior, such as attention deficit hyperactivity disorder (ADHD) and protect against the cell toxicity through oxidized dopamine. First, approximately 300 candidate HDACi compounds were added to the SH-SY5Y dopaminergic cell line to identify the possible changes in theVMAT2 expression levels, which were measured using quantitative polymerase chain reaction. The results demonstrated, that treatment with pimelic diphenylamide 106 (TC-H 106), a class I HDACi, increased VMAT2 expression in both the SH-SY5Y cells and mouse brain. The increased VMAT2 expression induced by TC-H 106 alleviated the cytotoxicity attributed to 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP+ ) and free dopamine treatment. Moreover, dopamine concentrations, both intracellularly and in the synaptosomes, were significantly elevated by increased VMAT2 expression. These results suggest that dopamine concentration regulation by VMAT2 expression induced by TC-H 106 could alter several related behavioral aspects that was confirmed by attenuation of hyperactivity and impulsivity, which were major characteristics of animal modelshowing ADHD-like behaviors. These results indicate that HDACi-increased VMAT2 expression offers sufficient protections against dopaminergic cell death induced by oxidative stress. Thus, the epigenetic approach could be considered as therapeutic candidate for neuropsychiatric disease regulation.

Iron chelation prevents nigrostriatal neurodegeneration in a chronic methamphetamine mice model

Methamphetamine (METH) has been established to selectively target and impair dopaminergic neurons through multiple pathways. Ferroptosis is a unique form of non-apoptotic cell death driven by cellular iron accumulation-induced lipid peroxidation. Nonetheless, it remains unclear whether METH can induce ferroptosis. In the present study, we sought to assess alterations in iron levels after chronic METH exposure and reveal the modulatory role of iron on METH-induced pathologies. Importantly, we demonstrated that METH increased iron deposition in the nigrostriatal system, including the substantia nigra (SN) and caudate putamen (CPu). Moreover, decreases in GPx4 levels, increases in lipid peroxidation products, and pathological alterations were observed in the nigrostriatal system as a consequence of chronic METH exposure. The iron chelator deferiprone not only alleviated nigrostriatal iron deposition, dopaminergic cell death, and lipid peroxidation, but alsoattenuated the decreases in GPx4 induced by METH. These findings suggest an alleviation of ferroptosis in dopaminergic neurons. In addition, we found that the ferroptosis inhibitor liproxstatin-1 attenuated METH-induced dopaminergic degeneration in the nigrostriatal system. Our findings corroborated that METH might induce dopaminergic neurodegeneration through iron-dependent ferroptosis. Interestingly, reducing iron levels or inhibiting ferroptosis may alleviate METH-induced dopaminergic neurodegeneration.

Lactoferrin: neuroprotection against Parkinson's disease and secondary molecule for potential treatment.

Parkinson's disease (PD) is the second-most common neurodegenerative disease and is largely caused by the death of dopaminergic (DA) cells. Dopamine loss occurs in the substantia nigra pars compacta and leads to dysfunctions in motor functions. Death of DA cells can occur with oxidative stress and dysfunction of glial cells caused by Parkinson-related gene mutations. Lactoferrin (Lf) is a multifunctional glycoprotein that is usually known for its presence in milk, but recent research shows that Lf is also found in the brain regions. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a known mitochondrial toxin that disturbs the mitochondrial electron transport chain (ETC) system and increases the rate of reactive oxygen species. Lf's high affinity for metals decreases the required iron for the Fenton reaction, reduces the oxidative damage to DA cells caused by MPTP, and increases their surveillance rate. Several studies also investigated Lf's effect on neurons that are treated with MPTP. The results pointed out that Lf's protective effect can also be observed without the presence of oxidative stress; thus, several potential mechanisms are currently being researched, starting with a potential HSPG-Lf interaction in the cellular membrane of DA cells. The presence of Lf activity in the brain region also showed that lactoferrin initiates receptor-mediated transcytosis in the blood-brain barrier (BBB) with the existence of lactoferrin receptors in the endothelial cells. The existence of Lf receptors both in endothelial cells and DA cells created the idea of using Lf as a secondary molecule in the transport of therapeutic agents across the BBB, especially in nanoparticle development.

Hsa-miR-320a mediated exosome release under PD stress conditions rescue mitochondrial ROS and cell death in the recipient neuronal and glial cells.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal cell death. Emerging evidence suggest exosomes as a crucial player in the progression and pathogenesis of PD via intercellular communication between different cell types in brain. Exosome release is enhanced from dysfunctional neurons/glia (source cells) under PD stress and mediates the transfer of biomolecules between different cell types (recipient) in brain leading to unique functional outcomes. Exosome release is modulated by alterations in the autophagy and lysosomal pathways; however, the molecular factors regulating these pathways remain elusive. Micro-RNAs (miRNAs) are class of non-coding RNAs that regulate gene expression post-transcriptionally by binding target mRNA and modulate its turnover and translation; however their role in modulating exosome release is not understood. Here, we analyzed the miRNAs-mRNAs network which target cellular processes regulating exosome release. hsa-miR-320a showed the maximum mRNA targets of autophagy, lysosome, mitochondria and exosome release pathways. hsa-miR-320a regulate ATG5 levels and modulate exosome release under PD stress conditions in neuronal SH-SY5Y and glial U-87 MG cells. hsa-miR-320a modulates autophagic flux, lysosomal functions, and mitochondrial ROS in neuronal SH-SY5Y and glial U-87 MG cells. Exosomes derived from hsa-miR-320a expressing source cells under PD stress conditions were actively internalized in the recipient cells and rescued cell death and mitochondrial ROS. These results suggest that hsa-miR-320a regulates autophagy and lysosomal pathways and modulates exosome release in the source cells and derived exosomes under PD stress conditions rescue cell death and mitochondrial ROS in the recipient neuronal and glial cells.

Pharmacological Inhibition of PTEN Rescues Dopaminergic Neurons by Attenuating Apoptotic and Neuroinflammatory Signaling Events.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta resulting in an irreversible and a debilitating motor dysfunction. Though both genetic and idiopathic factors are implicated in the disease etiology, idiopathic PD comprise the majority of clinical cases and is caused by exposure to environmental toxicants and oxidative stress. Fyn kinase activation has been identified as an early molecular signaling event that primes neuroinflammatory and neurodegenerative events associated with dopaminergic cell death. However, the upstream regulator of Fyn activation remains unidentified. We investigated whether the lipid and tyrosine phosphatase PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) could be the upstream regulator of Fyn activation in PD models as PTEN has been previously reported to contribute to Parkinsonian pathology. Our findings, using bioluminescence resonance energy transfer (BRET) and immunoblotting, indicate for the first time that PTEN is a critical early stress sensor in response to oxidative stress and neurotoxicants in in vitro models of PD. Pharmacological attenuation of PTEN activity rescues dopaminergic neurons from neurotoxicant-induced cytotoxicity by modulating Fyn kinase activation. Our findings also identify PTEN's novel roles in contributing to mitochondrial dysfunction which contribute to neurodegenerative processes. Interestingly, we found that PTEN positively regulates interleukin-1β (IL-1β) and the transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Taken together, we have identified PTEN as a disease course altering pharmacological target that may be further validated for the development of novel therapeutic strategies targeting PD.