Neuroprotective Effect of a DJ-1 Based Peptide in a Toxin Induced Mouse Model of Multiple System Atrophy.
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ABSTRACT:
SUBMITTER: Glat MJ
PROVIDER: S-EPMC4763099 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Multiple system atrophy (MSA) is a rare neurodegenerative disorder with unclear etiology, currently difficult and delayed diagnosis, and rapid progression, leading to disability and lethality within 6 to 9 years after symptom onset. The neuropathology of MSA classifies the disease in the group of a-synucleinopathies together with Parkinson's disease and other Lewy body disorders, but features specific oligodendroglial inclusions, which are pathognomonic for MSA. MSA has no efficient therapy to date. Development of experimental models is crucial to elucidate the disease mechanisms in progression and to provide a tool for preclinical screening of putative therapies for MSA. In vitro and in vivo models, based on selective neurotoxicity, a-synuclein oligodendroglial overexpression, and strain-specific propagation of a-synuclein fibrils, have been developed, reflecting various facets of MSA pathology. Over the years, the continuous exchange from bench to bedside and backward has been crucial for the advancing of MSA modelling, elucidating MSA pathogenic pathways, and understanding the existing translational gap to successful clinical trials in MSA. The review discusses specifically advantages and limitations of the PLP-a-syn mouse model of MSA, which recapitulates motor and non-motor features of the human disease with underlying striatonigral degeneration, degeneration of autonomic centers, and sensitized olivopontocerebellar system, strikingly mirroring human MSA pathology.
| S-EPMC10119356 | biostudies-literature
Project description:Spinal muscular atrophy (SMA) is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC), which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA. In this manuscript, we have demonstrated that TTC enhance the SMN expression in motor neurons "in vitro" and evaluated the effect of intramuscular injection of TTC-encoding plasmid in the spinal cord and the skeletal muscle of SMNdelta7 mice. For this purpose, we studied the weight and the survival time, as well as, the survival and cell death pathways and muscular atrophy. Our results showed that TTC treatment reduced the expression of autophagy markers (Becn1, Atg5, Lc3, and p62) and pro-apoptotic genes such as Bax and Casp3 in spinal cord. In skeletal muscle, TTC was able to downregulate the expression of the main marker of autophagy, Lc3, to wild-type levels and the expression of the apoptosis effector protein, Casp3. Regarding the genes related to muscular atrophy (Ankrd1, Calm1, Col19a1, Fbox32, Mt2, Myod1, NogoA, Pax7, Rrad, and Sln), TTC suggest a compensatory effect for muscle damage response, diminished oxidative stress and modulated calcium homeostasis. These preliminary findings suggest the need for further experiments to depth study the effect of TTC in SMA disease.
| S-EPMC4995219 | biostudies-literature
Project description:Multiple system atrophy (MSA) is a neurodegenerative disease caused by an accumulation of alpha-synuclein (alpha-syn) in oligodendrocytes. Little is known about the cellular mechanisms by which alpha-syn accumulation causes neuronal degeneration in MSA. Our previous research, however, revealed that in a mouse model of MSA, oligodendrocytic inclusions of alpha-syn induced neuronal accumulation of alpha-syn, as well as progressive neuronal degeneration. Here we identify the mechanisms that underlie neuronal accumulation of alpha-syn in a mouse MSA model. We found that the alpha-syn protein binds to beta-III tubulin in microtubules to form an insoluble complex. The insoluble alpha-syn complex progressively accumulates in neurons and leads to neuronal dysfunction. Furthermore, we demonstrated that the neuronal accumulation of insoluble alpha-syn is suppressed by treatment with a microtubule depolymerizing agent. The underlying pathological process appeared to also be inhibited by this treatment, providing promise for future therapeutic approaches.
| S-EPMC2671377 | biostudies-literature
Project description:Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (α-syn) cytoplasmic inclusions located within oligodendroglia. Neuroinflammation, demyelination, and neurodegeneration are correlated with areas of glia cytoplasmic inclusions (GCI) pathology, however it is not known what specifically drives disease pathogenesis. Recent studies have shown that disease pathologies found in post-mortem tissue from MSA patients can be modeled in rodents via a modified AAV overexpressing α-syn, Olig001-SYN, which has a 95% tropism for oligodendrocytes. In the Olig001-SYN mouse model, CD4+ T cells have been shown to drive neuroinflammation and demyelination, however the mechanism by which this occurs remains unclear. In this study we use genetic and pharmacological approaches in the Olig001-SYN model of MSA to show that the pro-inflammatory cytokine interferon gamma (IFNγ) drives neuroinflammation, demyelination, and neurodegeneration. Furthermore, using an IFNγ reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFNγ in response to α-syn overexpression in oligodendrocytes. Results from these studies indicate that IFNγ expression from CD4+ T cells drives α-syn-mediated neuroinflammation, demyelination, and neurodegeneration. These results indicate that targeting IFNγ expression may be a potential disease modifying therapeutic strategy for MSA.
| S-EPMC10797897 | biostudies-literature
Project description:Mesenchymal stem cells (MSC) are currently strong candidates for cell-based therapies. They are well known for their differentiation potential and immunoregulatory properties and have been proven to be potentially effective in the treatment of a large variety of diseases, including neurodegenerative disorders. Currently there is no treatment that provides consistent long-term benefits for patients with multiple system atrophy (MSA), a fatal late onset ?-synucleinopathy. Principally neuroprotective or regenerative strategies, including cell-based therapies, represent a powerful approach for treating MSA. In this study we investigated the efficacy of intravenously applied MSCs in terms of behavioural improvement, neuroprotection and modulation of neuroinflammation in the (PLP)-?synuclein (?SYN) MSA model.MSCs were intravenously applied in aged (PLP)-?SYN transgenic mice. Behavioural analyses, defining fine motor coordination and balance capabilities as well as stride length analysis, were performed to measure behavioural outcome. Neuroprotection was assessed by quantifying TH neurons in the substantia nigra pars compacta (SNc). MSC treatment on neuroinflammation was analysed by cytokine measurements (IL-1?, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, GM-CSF, INF?, MCP-1, TGF-?1, TNF-?) in brain lysates together with immunohistochemistry for T-cells and microglia. Four weeks post MSC treatment we observed neuroprotection in the SNc, as well as downregulation of cytokines involved in neuroinflammation. However, there was no behavioural improvement after MSC application.To our knowledge this is the first experimental approach of MSC treatment in a transgenic MSA mouse model. Our data suggest that intravenously infused MSCs have a potent effect on immunomodulation and neuroprotection. Our data warrant further studies to elucidate the efficacy of systemically administered MSCs in transgenic MSA models.
| S-EPMC3097217 | biostudies-literature
Project description:Multiple system atrophy (MSA) is a rare, neurodegenerative disorder with rapid motor and non-motor symptom progression. MSA is characterized by protein aggregations of α-synuclein found in the cytoplasm of oligodendrocytes. Despite this pathological hallmark, there is still little known about the cause of this disease, resulting in poor treatment options and quality of life post-diagnosis. In this study, we investigated differentially expressed genes via RNA-sequencing of brain samples from a validated PLP-α-synuclein transgenic mouse model, identifying a total of 40 DEGs in the MSA group compared to control, with top detected genes being Gm15446, Mcm6, Aldh7a1 and Gm3435. We observed a significant enrichment of immune pathways and endothelial cell genes among the upregulated genes, whereas downregulated genes were significantly enriched for oligodendrocyte and neuronal genes. We then calculated possible overlap of these DEGs with previously profiled human MSA RNA, resulting in the identification of significant downregulation of the Tsr2 gene. Identifying key gene expression profiles specific to MSA patients is crucial to further understanding the cause, and possible prevention, of this rapidly progressive neurodegenerative disorder.
2024-11-07 | GSE247259 | GEO
Project description:Multiple system atrophy (MSA) is a fatal rapidly progressive α-synucleinopathy, characterized by prominent α-synuclein accumulation in oligodendrocytes. In this study we investigated mRNA expression in substantia nigra of MSA transgenic mice (Tg(Plp1-SNCA)1Haa) and wild type controls. This forms part of a larger study in which we investigated miRNA-mRNA regulatory network in substantia nagra and striatum of MSA transgenic mice in pre-motor stage of neurodegenration.
2016-03-15 | E-MTAB-3985 | biostudies-arrayexpress
Project description:Neuroinflammation plays a significant role in amyotrophic lateral sclerosis (ALS) pathology, leading to the development of therapies targeting inflammation in recent years. Our group has studied the tetanus toxin C-terminal fragment (TTC) as a therapeutic molecule, showing neuroprotective properties in the SOD1G93A mouse model. However, it is unknown whether TTC could have some effect on inflammation. The objective of this study was to assess the effect of TTC on the regulation of inflammatory mediators to elucidate its potential role in modulating inflammation occurring in ALS. After TTC treatment in SOD1G93A mice, levels of eotaxin-1, interleukin (IL)-2, IL-6 and macrophage inflammatory protein (MIP)-1 alpha (α) and galectin-1 were analyzed by immunoassays in plasma samples, whilst protein expression of caspase-1, IL-1β, IL-6 and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) was measured in the spinal cord, extensor digitorum longus (EDL) muscle and soleus (SOL) muscle. The results showed reduced levels of IL-6 in spinal cord, EDL and SOL in treated SOD1G93A mice. In addition, TTC showed a different role in the modulation of NLRP3 and caspase-1 depending on the tissue analyzed. In conclusion, our results suggest that TTC could have a potential anti-inflammatory effect by reducing IL-6 levels in tissues drastically affected by the disease. However, further research is needed to study more in depth the anti-inflammatory effect of TTC in ALS.
| S-EPMC7290364 | biostudies-literature
Project description:Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (α-syn) in oligodendrocytes accompanied by inflammation, demyelination, and subsequent synapse and neuronal loss. Little is known about the mechanisms of neurodegeneration in MSA. However, recent work has highlighted the important role of the immune system to the pathophysiology of other synuclein-related diseases such as Parkinson's disease. In this study, we investigated postmortem brain tissue from MSA patients and control subjects for evidence of immune activation in the brain. We found a significant increase of HLA-DR+ microglia in the putamen and substantia nigra of MSA patient tissue compared to controls, as well as significant increases in CD3+, CD4+, and CD8+ T cells in these same brain regions. To model MSA in vivo, we utilized a viral vector that selectively overexpresses α-syn in oligodendrocytes (Olig001-SYN) with > 95% tropism in the dorsal striatum of mice, resulting in demyelination and neuroinflammation similar to that observed in human MSA. Oligodendrocyte transduction with this vector resulted in a robust inflammatory response, which included increased MHCII expression on central nervous system (CNS) resident microglia, and infiltration of pro-inflammatory monocytes into the CNS. We also observed robust infiltration of CD4 T cells into the CNS and antigen-experienced CD4 T cells in the draining cervical lymph nodes. Importantly, genetic deletion of TCR-β or CD4 T cells attenuated α-syn-induced inflammation and demyelination in vivo. These results suggest that T cell priming and infiltration into the CNS are key mechanisms of disease pathogenesis in MSA, and therapeutics targeting T cells may be disease modifying.
| S-EPMC7181566 | biostudies-literature
Project description:Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the pathological accumulation of alpha-synuclein (?-syn) within oligodendroglial cells. This accumulation is accompanied by neuroinflammation with astrogliosis and microgliosis, that leads to neuronal death and subsequent parkinsonism and dysautonomia. Antidepressants have been explored as neuroprotective agents as they normalize neurotrophic factor levels, increase neurogenesis and reduce neurodegeneration, but their anti-inflammatory properties have not been fully characterized. We analyzed the anti-inflammatory profiles of three different antidepressants (fluoxetine, olanzapine and amitriptyline) in the MBP1-h?-syn transgenic (tg) mouse model of MSA. We observed that antidepressant treatment decreased the number of ?-syn-positive cells in the basal ganglia of 11-month-old tg animals. This reduction was accompanied with a similar decrease in the colocalization of ?-syn with astrocyte markers in this brain structure. Consistent with these results, antidepressants reduced astrogliosis in the hippocampus and basal ganglia of the MBP1-h?-syn tg mice, and modulated the expression levels of key cytokines that were dysregulated in the tg mouse model, such as IL-1?. In vitro experiments in the astroglial cell line C6 confirmed that antidepressants inhibited NF-?B translocation to the nucleus and reduced IL-1? protein levels. We conclude that the anti-inflammatory properties of antidepressants in the MBP1-h?-syn tg mouse model of MSA might be related to their ability to inhibit ?-syn propagation from oligodendrocytes to astroglia and to regulate transcription factors involved in cytokine expression. Our results suggest that antidepressants might be of interest as anti-inflammatory and ?-syn-reducing agents for MSA and other ?-synucleinopathies.
| S-EPMC4183229 | biostudies-literature