Correction to: Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson's disease model.
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SUBMITTER: Zhu C
PROVIDER: S-EPMC8265003 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimWe have previously reported that cambinol (DDL-112), a known inhibitor of neutral sphingomyelinase-2 (nSMase2), suppressed extracellular vesicle (EV)/exosome production in vitro in a cell model and reduced tau seed propagation. The enzyme nSMase2 is involved in the production of exosomes carrying proteopathic seeds and could contribute to cell-to-cell transmission of pathological protein aggregates implicated in neurodegenerative diseases such as Parkinson's disease (PD). Here, we performed in vivo studies to determine if DDL-112 can reduce brain EV/exosome production and proteopathic alpha synuclein (αSyn) spread in a PD mouse model.MethodsThe acute effects of single-dose treatment with DDL-112 on interleukin-1β-induced extracellular vesicle (EV) release in brain tissue of Thy1-αSyn PD model mice and chronic effects of 5 week DDL-112 treatment on behavioral/motor function and proteinase K-resistant αSyn aggregates in the PD model were determined.Results/discussionIn the acute study, pre-treatment with DDL-112 reduced EV/exosome biogenesis and in the chronic study, treatment with DDL-112 was associated with a reduction in αSyn aggregates in the substantia nigra and improvement in motor function. Inhibition of nSMase2 thus offers a new approach to therapeutic development for neurodegenerative diseases with the potential to reduce the spread of disease-specific proteopathic proteins.
| S-EPMC8056538 | biostudies-literature
Project description:Recently, extracellular vesicles (EVs), such as exosomes, have been proposed to play an influential role in the cell-to-cell spread of neurodegenerative diseases, including the intercellular transmission of α-synuclein (α-syn). However, the regulation of EV biogenesis and its relation to Parkinson's disease (PD) is only partially understood. The generation of EVs through the ESCRT-independent pathway depends on the hydrolysis of sphingomyelin by neutral sphingomyelinase 2 (nSMase2) to produce ceramide, which causes the membrane of endosomal multivesicular bodies to bud inward. nSMase2 is sensitive to oxidative stress, a common process in PD brains; however, little is known about the role of sphingomyelin metabolism in the pathogenesis of PD. This is the first study to show that inhibiting nSMase2 decreases the transfer of oligomeric aggregates of α-syn between neuron-like cells. Furthermore, it reduced the accumulation and aggregation of high-molecular-weight α-syn. Hypoxia, as a model of oxidative stress, reduced the levels of nSMase2, but not its enzymatic activity, and significantly altered the lipid composition of cells without affecting EV abundance or the transfer of α-syn. These data show that altering sphingolipids can mitigate the spread of α-syn, even under hypoxic conditions, potentially suppressing PD progression.
| S-EPMC6724746 | biostudies-literature
Project description:Silica nanoparticles (SiO2 NPs) are increasingly investigated for their potential in drug delivery systems. However, the neurotoxicity of SiO2 NPs remains to be fully clarified. Previously SiO2 NPs have been reported to be detected in the central nervous system, especially in the dopaminergic neurons which are deeply involved in Parkinson's disease (PD). In this article, we characterized the effects of SiO2 NPs on inducing PD-like pathology both in vitro and in vivo. Results showed that SiO2 NPs promote more severe hyperphosphorylation and aggregation of α-synuclein, mitochondria impairment, oxidative stress, autophagy dysfunction, and neuronal apoptosis in the α-Syn A53T transgenic mice intranasally administrated with SiO2 NPs compared with the control group. Our findings provide new evidence supporting that SiO2 NPs exposure might have a strong capability of promoting the initiation and development of PD.
| S-EPMC8792744 | biostudies-literature
Project description:Intraneuronal inclusions of misfolded α-synuclein (α-syn) and prion-like spread of the pathologic α-syn contribute to progressive neuronal death in Parkinson's disease (PD). Despite the pathologic significance, no efficient therapeutic intervention targeting α-synucleinopathy has been developed. In this study, we provide evidence that astrocytes, especially those cultured from the ventral midbrain (VM), show therapeutic potential to alleviate α-syn pathology in multiple in vitro and in vivo α-synucleinopathic models. Regulation of neuronal α-syn proteostasis underlies the therapeutic function of astrocytes. Specifically, VM-derived astrocytes inhibited neuronal α-syn aggregation and transmission in a paracrine manner by correcting not only intraneuronal oxidative and mitochondrial stresses but also extracellular inflammatory environments, in which α-syn proteins are prone to pathologic misfolding. The astrocyte-derived paracrine factors also promoted disassembly of extracellular α-syn aggregates. In addition to the aggregated form of α-syn, VM astrocytes reduced total α-syn protein loads both by actively scavenging extracellular α-syn fibrils and by a paracrine stimulation of neuronal autophagic clearance of α-syn. Transplantation of VM astrocytes into the midbrain of PD model mice alleviated α-syn pathology and protected the midbrain dopamine neurons from neurodegeneration. We further showed that cografting of VM astrocytes could be exploited in stem cell-based therapy for PD, in which host-to-graft transmission of α-syn pathology remains a critical concern for long-term cell therapeutic effects.
| S-EPMC9304026 | biostudies-literature
Project description:Aberrant α-synuclein (α-Syn) accumulation resulting from proteasome dysfunction is considered as a prominent factor to initiate and aggravate the neurodegeneration in Parkinson's disease (PD). Although the involvement of 26S proteasome in proteostasis imbalance has been widely accepted, our knowledge about the regulation of immunoproteasome function and its potential role in α-Syn pathology remains limited. Immunoproteasome abundance and proteolytic activities depend on the finely tuned assembly process, especially β-ring formation mediated by the only well-known chaperone proteasome maturation protein (POMP). Here, we identified that α-Syn overexpression was associated with a reduction in immunoproteasome function, which in turn limited the degradation of polo-like kinase 2 (PLK2), exacerbated α-Syn Ser129 phosphorylation and aggregation, ultimately leading to the neurodegeneration. These effects could be dramatically attenuated by β5i overexpression. Mechanistically, α-Syn suppressed the transcriptional regulation of POMP by nuclear factor erythroid 2-related factor 2 (NRF2), thereby preventing the assembly of immunoproteasome β subunits. Dopaminergic neurons-specific overexpression of NRF2-POMP axis effectively rescued the aggregation of α-Syn and PD-like phenotypes. These findings characterized abnormal immunoproteasome assembly as a key contributor governing α-Syn accumulation and neurodegeneration, which might open up a new perspective for the implication of immunoproteasome in PD and provide approaches of manipulating immunoproteasome assembly for therapeutic purposes.
| S-EPMC8577461 | biostudies-literature
Project description:BackgroundOverexpression and abnormal accumulation of aggregated alpha-synuclein (alphaS) have been linked to Parkinson's disease (PD) and other synucleinopathies. alphaS can misfold and adopt a variety of morphologies but recent studies implicate oligomeric forms as the most cytotoxic species. Both genetic mutations and chronic exposure to neurotoxins increase alphaS aggregation and intracellular reactive oxygen species (ROS), leading to mitochondrial dysfunction and oxidative damage in PD cell models.ResultsHere we show that curcumin can alleviate alphaS-induced toxicity, reduce ROS levels and protect cells against apoptosis. We also show that both intracellular overexpression of alphaS and extracellular addition of oligomeric alphaS increase ROS which induces apoptosis, suggesting that aggregated alphaS may induce similar toxic effects whether it is generated intra- or extracellulary.ConclusionsSince curcumin is a natural food pigment that can cross the blood brain barrier and has widespread medicinal uses, it has potential therapeutic value for treating PD and other neurodegenerative disorders.
| S-EPMC2879277 | biostudies-literature
Project description:The key aspect of the classification of neurodegenerative diseases is the histopathological detection of certain proteins in the brain. The various disease entities are distinguished with respect to the type of detected protein and with respect to the configuration and localization of the corresponding protein aggregates. Aggregates of alpha-synuclein (ASYN) are the defining hallmark of several neurodegenerative disorders termed synucleinopathies. The most well-known diseases in this spectrum are Parkinson's disease (PD) with neuronal detection of Lewy bodies, dementia with Lewy bodies (DLB), with additional detection of beta-amyloid and multiple system atrophy (MSA), where ASYN aggregates are found in glia cells in the form of Papp-Lantos inclusions. ASYN has been identified as a key target for the development of therapeutic approaches to synucleinopathies given its central role in the pathophysiology of these diseases. Current treatment strategies can be roughly classified into six groups: 1) lowering ASYN expression (antisense therapy), 2) inhibition of formation of toxic ASYN aggregates (aggregation inhibitors, chelators), 3) dissolving or removal of intracellular or extracellular toxic AYSN aggregates (active and passive immunotherapy, aggregation inhibitors), 4) enhancement of cellular clearance mechanisms (autophagy, lysosomal microphagy) for removal of toxic forms of alpha-synuclein, 5) modulation of neuroinflammatory processes and 6) neuroprotective strategies. This article summarizes the current therapeutic approaches and sheds light on promising future treatment approaches.
| S-EPMC8648656 | biostudies-literature
Project description:α-Synuclein is implicated both in physiological functions at neuronal synaptic terminals as well as in pathological processes in the context of Parkinson's disease. However, the molecular mechanisms for these apparently diverse roles are unclear. Here we show that specific RNA transcript isoforms of α-synuclein with an extended 3' untranslated region, termed aSynL, appear selectively linked to pathological processes, relative to shorter α-synuclein transcripts. Common variants in the aSynL 3' untranslated region associated with Parkinson's disease risk promote the accumulation and translation of aSynL transcripts. The presence of intracellular dopamine can further enhance the relative abundance of aSynL transcripts through alternative polyadenylation site selection. We demonstrate that the presence of the extended aSynL transcript 3' untranslated region impacts accumulation of α-synuclein protein, which appears redirected away from synaptic terminals and towards mitochondria, reminiscent of Parkinson's disease pathology. Taken together, these findings identify a novel mechanism for aSyn regulation in the context of Parkinson's disease-associated genetic and environmental variations.
| S-EPMC3660047 | biostudies-literature
Project description:Oligomeric forms of alpha-synuclein are emerging as key mediators of pathogenesis in Parkinson's disease. Our understanding of the exact contribution of alpha-synuclein oligomers to disease is limited by the lack of a technique for their specific detection. We describe a novel method, the alpha-synuclein proximity ligation assay, which specifically recognizes alpha-synuclein oligomers. In a blinded study with post-mortem brain tissue from patients with Parkinson's disease (n = 8, age range 73-92 years, four males and four females) and age- and sex-matched controls (n = 8), we show that the alpha-synuclein proximity ligation assay reveals previously unrecognized pathology in the form of extensive diffuse deposition of alpha-synuclein oligomers. These oligomers are often localized, in the absence of Lewy bodies, to neuroanatomical regions mildly affected in Parkinson's disease. Diffuse alpha-synuclein proximity ligation assay signal is significantly more abundant in patients compared to controls in regions including the cingulate cortex (1.6-fold increase) and the reticular formation of the medulla (6.5-fold increase). In addition, the alpha-synuclein proximity ligation assay labels very early perikaryal aggregates in morphologically intact neurons that may precede the development of classical Parkinson's disease lesions, such as pale bodies or Lewy bodies. Furthermore, the alpha-synuclein proximity ligation assay preferentially detects early-stage, loosely compacted lesions such as pale bodies in patient tissue, whereas Lewy bodies, considered heavily compacted late lesions are only very exceptionally stained. The alpha-synuclein proximity ligation assay preferentially labels alpha-synuclein oligomers produced in vitro compared to monomers and fibrils, while stained oligomers in human brain display a distinct intermediate proteinase K resistance, suggesting the detection of a conformer that is different from both physiological, presynaptic alpha-synuclein (proteinase K-sensitive) and highly aggregated alpha-synuclein within Lewy bodies (proteinase K-resistant). These disease-associated conformers represent previously undetected Parkinson's disease pathology uncovered by the alpha-synuclein proximity ligation assay.
| S-EPMC4614141 | biostudies-literature
Project description:?-Synuclein (?-syn) has been genetically and biochemically linked to the pathogenesis of Parkinson's disease (PD). There is accumulating evidence that misfolded ?-syn species spread between cells in a prion-like manner and seed the aggregation of endogenous protein in the recipient cells. Exosomes have been proposed to mediate the transfer of misfolded ?-syn and thus facilitate disease transmission, although the pathological mechanism remains elusive. Here, we investigated the seeding capacity of exosome-associated ?-syn, in vivo. Disease-associated ?-syn was present in exosome fractions isolated from transgenic A53T mouse brain. However, following intrastriatal injection of such exosomes in wild-type (wt) mice, we were not able to detect any accumulation of endogenous ?-syn. In addition, recombinant fibrillar ?-syn, when loaded to isolated brain exosomes, induced minor pathological ?-syn brain accumulation at 7 months post injection. These data suggest that exosomes neutralize the effect of toxic ?-syn species and raise additional questions on their paracrine modulatory role in disease transmission.
| S-EPMC7186405 | biostudies-literature