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rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration.
Mol Neurodegener. 2013 Nov 25; 8:44.MN

Abstract

BACKGROUND

Alpha-synuclein is a key protein implicated in the pathogenesis of Parkinson's disease (PD). It is the main component of the Lewy bodies, a cardinal neuropathological feature in the disease. In addition, whole locus multiplications and point mutations in the gene coding for alpha-synuclein lead to autosomal dominant monogenic PD. Over the past decade, research on PD has impelled the development of new animal models based on alpha-synuclein. In this context, transgenic mouse lines have failed to reproduce several hallmarks of PD, especially the strong and progressive dopaminergic neurodegeneration over time that occurs in the patients. In contrast, viral vector-based models in rats and non-human primates display prominent, although highly variable, nigral dopaminergic neuron loss. However, the few studies available on viral vector-mediated overexpression of alpha-synuclein in mice report a weak neurodegenerative process and no clear Lewy body-like pathology. To address this issue, we performed a comprehensive comparative study of alpha-synuclein overexpression by means of recombinant adeno-associated viral vectors serotype 2/7 (rAAV2/7) at different doses in adult mouse substantia nigra.

RESULTS

We noted a significant and dose-dependent alpha-synucleinopathy over time upon nigral viral vector-mediated alpha-synuclein overexpression. We obtained a strong, progressive and dose-dependent loss of dopaminergic neurons in the substantia nigra, reaching a maximum of 82% after 8 weeks. This effect correlated with a reduction in tyrosine hydroxylase immunoreactivity in the striatum. Moreover, behavioural analysis revealed significant motor impairments from 12 weeks after injection on. In addition, we detected the presence of alpha-synuclein-positive aggregates in the remaining surviving neurons. When comparing wild-type to mutant A53T alpha-synuclein at the same vector dose, both induced a similar degree of cell death. These data were supported by a biochemical analysis that showed a net increase in soluble and insoluble alpha-synuclein expression over time to the same extent for both alpha-synuclein variants.

CONCLUSIONS

In conclusion, our in vivo data provide evidence that strong and significant alpha-synuclein-induced neuropathology and progressive dopaminergic neurodegeneration can be achieved in mouse brain by means of rAAV2/7.

Authors+Show Affiliations

Department of Neurosciences and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, Laboratory for Neurobiology and Gene Therapy, Kapucijnenvoer 33, box 7001, 3000 Leuven, Belgium. veerle.baekelandt@med.kuleuven.be.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24267638

Citation

Oliveras-Salvá, Marusela, et al. "RAAV2/7 Vector-mediated Overexpression of Alpha-synuclein in Mouse Substantia Nigra Induces Protein Aggregation and Progressive Dose-dependent Neurodegeneration." Molecular Neurodegeneration, vol. 8, 2013, p. 44.
Oliveras-Salvá M, Van der Perren A, Casadei N, et al. RAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration. Mol Neurodegener. 2013;8:44.
Oliveras-Salvá, M., Van der Perren, A., Casadei, N., Stroobants, S., Nuber, S., D'Hooge, R., Van den Haute, C., & Baekelandt, V. (2013). RAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration. Molecular Neurodegeneration, 8, 44. https://doi.org/10.1186/1750-1326-8-44
Oliveras-Salvá M, et al. RAAV2/7 Vector-mediated Overexpression of Alpha-synuclein in Mouse Substantia Nigra Induces Protein Aggregation and Progressive Dose-dependent Neurodegeneration. Mol Neurodegener. 2013 Nov 25;8:44. PubMed PMID: 24267638.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration. AU - Oliveras-Salvá,Marusela, AU - Van der Perren,Anke, AU - Casadei,Nicolas, AU - Stroobants,Stijn, AU - Nuber,Silke, AU - D'Hooge,Rudi, AU - Van den Haute,Chris, AU - Baekelandt,Veerle, Y1 - 2013/11/25/ PY - 2013/04/27/received PY - 2013/11/18/accepted PY - 2013/11/26/entrez PY - 2013/11/26/pubmed PY - 2014/8/2/medline SP - 44 EP - 44 JF - Molecular neurodegeneration JO - Mol Neurodegener VL - 8 N2 - BACKGROUND: Alpha-synuclein is a key protein implicated in the pathogenesis of Parkinson's disease (PD). It is the main component of the Lewy bodies, a cardinal neuropathological feature in the disease. In addition, whole locus multiplications and point mutations in the gene coding for alpha-synuclein lead to autosomal dominant monogenic PD. Over the past decade, research on PD has impelled the development of new animal models based on alpha-synuclein. In this context, transgenic mouse lines have failed to reproduce several hallmarks of PD, especially the strong and progressive dopaminergic neurodegeneration over time that occurs in the patients. In contrast, viral vector-based models in rats and non-human primates display prominent, although highly variable, nigral dopaminergic neuron loss. However, the few studies available on viral vector-mediated overexpression of alpha-synuclein in mice report a weak neurodegenerative process and no clear Lewy body-like pathology. To address this issue, we performed a comprehensive comparative study of alpha-synuclein overexpression by means of recombinant adeno-associated viral vectors serotype 2/7 (rAAV2/7) at different doses in adult mouse substantia nigra. RESULTS: We noted a significant and dose-dependent alpha-synucleinopathy over time upon nigral viral vector-mediated alpha-synuclein overexpression. We obtained a strong, progressive and dose-dependent loss of dopaminergic neurons in the substantia nigra, reaching a maximum of 82% after 8 weeks. This effect correlated with a reduction in tyrosine hydroxylase immunoreactivity in the striatum. Moreover, behavioural analysis revealed significant motor impairments from 12 weeks after injection on. In addition, we detected the presence of alpha-synuclein-positive aggregates in the remaining surviving neurons. When comparing wild-type to mutant A53T alpha-synuclein at the same vector dose, both induced a similar degree of cell death. These data were supported by a biochemical analysis that showed a net increase in soluble and insoluble alpha-synuclein expression over time to the same extent for both alpha-synuclein variants. CONCLUSIONS: In conclusion, our in vivo data provide evidence that strong and significant alpha-synuclein-induced neuropathology and progressive dopaminergic neurodegeneration can be achieved in mouse brain by means of rAAV2/7. SN - 1750-1326 UR - https://www.unboundmedicine.com/medline/citation/24267638/rAAV2/7_vector_mediated_overexpression_of_alpha_synuclein_in_mouse_substantia_nigra_induces_protein_aggregation_and_progressive_dose_dependent_neurodegeneration_ L2 - https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-8-44 DB - PRIME DP - Unbound Medicine ER -