Investigating the neuroprotective effect of AAV-mediated β-synuclein overexpression in a transgenic model of synucleinopathy

Sargent, Dorian; Bétemps, Dominique; Drouyer, Matthieu; Verchère, Jérémy; Gaillard, Damien; Arsac, Jean-Noël; Lakhdar, Latifa; Salvetti, Anna; Baron, Thierry

doi:10.1038/s41598-018-35825-2

Cited by 6 publications

(3 citation statements)

References 36 publications

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“…We found that intracerebral inoculations of brain extracts from old and sick M83 mice drastically accelerated the onset of paralysis that typically develops during the ageing of these mice [7]. These observations were then confirmed in a number of other studies, either after intracerebral inoculations of fibrillar recombinant aS [8][9][10] or of brain extracts from human patients, notably with MSA [11][12][13]. Other studies used different peripheral inoculation routes [14][15][16][17] with similar findings.…”

Section: Introductionsupporting

confidence: 80%

Protease-Sensitive and -Resistant Forms of Human and Murine Alpha-Synucleins in Distinct Brain Regions of Transgenic Mice (M83) Expressing the Human Mutated A53T Protein

Bétemps,

Arsac,

Nicot

et al. 2023

Biomolecules

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Human neurodegenerative diseases associated with the misfolding of the alpha-synuclein (aS) protein (synucleinopathies) are similar to prion diseases to the extent that lesions are spread by similar molecular mechanisms. In a transgenic mouse model (M83) overexpressing a mutated (A53T) form of human aS, we had previously found that Protein Misfolding Cyclic Amplification (PMCA) triggered the aggregation of aS, which is associated with a high resistance to the proteinase K (PK) digestion of both human and murine aS, a major hallmark of the disease-associated prion protein. In addition, PMCA was also able to trigger the aggregation of murine aS in C57Bl/6 mouse brains after seeding with sick M83 mouse brains. Here, we show that intracerebral inoculations of M83 mice with C57Bl/6-PMCA samples strikingly shortens the incubation period before the typical paralysis that develops in this transgenic model, demonstrating the pathogenicity of PMCA-aggregated murine aS. In the hind brain regions of these sick M83 mice containing lesions with an accumulation of aS phosphorylated at serine 129, aS also showed a high PK resistance in the N-terminal part of the protein. In contrast to M83 mice, old APPxM83 mice co-expressing human mutated amyloid precursor and presenilin 1 proteins were seen to have an aggregation of aS, especially in the cerebral cortex, hippocampus and striatum, which also contained the highest load of aS phosphorylated at serine 129. This was proven by three techniques: a Western blot analysis of PK-resistant aS; an ELISA detection of aS aggregates; or the identification of aggregates of aS using immunohistochemical analyses of cytoplasmic/neuritic aS deposits. The results obtained with the D37A6 antibody suggest a higher involvement of murine aS in APPxM83 mice than in M83 mice. Our study used novel tools for the molecular study of synucleinopathies, which highlight similarities with the molecular mechanisms involved in prion diseases.

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Section: Introductionsupporting

confidence: 80%

Protease-Sensitive and -Resistant Forms of Human and Murine Alpha-Synucleins in Distinct Brain Regions of Transgenic Mice (M83) Expressing the Human Mutated A53T Protein

Bétemps,

Arsac,

Nicot

et al. 2023

Biomolecules

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“… 27 They also include beta‐synuclein, which plays a detrimental role in Alzheimer's disease and Parkinson's disease. 28 Nevertheless, agents that have the potential to reduce excitotoxicity are currently under investigation as promising HIE therapies. 29 …”

Section: Discussionmentioning

confidence: 99%

Proteomic profiles in cerebrospinal fluid predicted death and disability in term infants with perinatal asphyxia: A pilot study

et al. 2022

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Aim Perinatal asphyxia, resulting in hypoxic‐ischaemic encephalopathy (HIE), has been associated with high mortality rates and severe lifelong neurodevelopmental disabilities. Our aim was to study the association between the proteomic profile in cerebrospinal fluid (CSF) and the degree of HIE and long‐term outcomes. Methods We prospectively enrolled 18‐term born infants with HIE and 10‐term born controls between 2000 and 2004 from the Karolinska University Hospital. An antibody suspension bead array and FlexMap3D analysis was used to characterise 178 unique brain‐derived and inflammation associated proteins in their CSF. Results Increased CSF concentrations of several brain‐specific proteins were observed in the proteome of HIE patients compared with the controls. An upregulation of neuroinflammatory pathways was also noted and this was confirmed by pathway analysis. Principal component analysis revealed a gradient from favourable to unfavourable HIE grades and outcomes. The proteins that provided strong predictors were structural proteins, including myelin basic protein and alpha‐II spectrin. The functional proteins included energy‐related proteins like neuron‐specific enolase and synaptic regulatory proteins. Increased CSF levels of 51 proteins correlated with adverse outcomes in infants with HIE. Conclusion Brain‐specific proteins and neuroinflammatory mediators in CSF may predict HIE degrees and outcomes after perinatal asphyxia.

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“…For patients with lifelong genetic disorders, such a decrease could reduce the concentration of gene products outside the therapeutic window. On the other hand, simply increasing the dose of AAV at the first administration may lead to vector toxicity 26 , an immune response against both vector 27 and transgene 28 , and potentially the side effects from overexpression of the transgene 29 .…”

Section: Introductionmentioning

confidence: 99%

Immune profiling of adeno-associated virus response identifies B cell-specific targets that enable vector re-administration in mice

et al. 2022

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Adeno-associated virus (AAV) vector-based gene therapies can be applied to a wide range of diseases. AAV expression can last for months to years, but vector re-administration may be necessary to achieve life-long treatment. Unfortunately, immune system response against these vectors is potentiated after the first administration, which prevents the clinical use of repeated administration of AAVs. Reducing immune response against AAVs while minimizing immunosuppression would improve gene delivery efficiency and long-term safety. In this study, we quantified the contributions of multiple immune system components towards AAV response in mice. We identified B-cell-mediated immunity as a critical component preventing vector readministration. Specifically, we found that IgG depletion was insufficient to enhance readministration, suggesting the key role of B-cell mediated IgM antibodies in the immune response against AAV. Further, we also found that AAV-mediated transduction is improved compared to wild-type mice in µMT mice that lack functional IgM heavy chains and cannot form mature Bcells. Combined, our results suggest that IgM production in B cells is a potential target for therapeutics enabling AAV re-administration. Our results also suggest that the µMT mice are a potentially useful experimental model for gene delivery studies since they allow for up to 15-fold more efficient gene delivery.

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Investigating the neuroprotective effect of AAV-mediated β-synuclein overexpression in a transgenic model of synucleinopathy

Cited by 6 publications

References 36 publications

Protease-Sensitive and -Resistant Forms of Human and Murine Alpha-Synucleins in Distinct Brain Regions of Transgenic Mice (M83) Expressing the Human Mutated A53T Protein

Protease-Sensitive and -Resistant Forms of Human and Murine Alpha-Synucleins in Distinct Brain Regions of Transgenic Mice (M83) Expressing the Human Mutated A53T Protein

Proteomic profiles in cerebrospinal fluid predicted death and disability in term infants with perinatal asphyxia: A pilot study

Immune profiling of adeno-associated virus response identifies B cell-specific targets that enable vector re-administration in mice

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