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Direct MRI-guided stereotaxic viral mediated gene transfer of alpha-synuclein in the Gottingen minipig CNS

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Glud A. N., Hedegaard C., Nielsen M. S., Sorensen J. C., Bendixen C., Jensen P. H., Mogensen P. H., Larsen K., Bjarkam C. R.

Acta Neurobiologiae Experimentalis

2011

tom 71

nr 4

The aim was to establish a non-primate large animal PD model by lentiviral vector mediated mutant alpha-synuclein overexpression in the substantia nigra. Lentivirus encoding A53T alpha-synuclein (6 x 2.5 ^l) was stereotaxically injected into the substantia nigra of six adult female Gottingen minipigs. Contralateral control injections encoding enhanced green fluorescent protein (EGFP) were performed. Gait-analysis was performed pre- and postoperatively. PCR of the transgenes and immunohistochemical staining against alpha-synuclein, EGFP, GFAP and TH was performed after 20 weeks. Gait- analysis revealed a significant increase in step length and height, and a decrease in the double stand phase. PCR verified the mesencephalic presence of transgenes. IHC analysis showed alpha-synuclein expression in nigral neurons, around the injection tract and in related nigrostriatal projections. The alpha-synuclein positive neurons appeared swollen and vacuolated, in contrast to the EGFP-injected control side. To transduct all nigrostriatal cells with few microinjections, wider dissemination of the transgene must be achieved.

Direct gene transfer in the Göttingen minipig CNS using stereotaxic lentiviral microinjections

100%

Glud A. N., Hedegaard C., Nielsen M. S., Sorensen J. C., Bendixen C., Jensen P. H., Larsen K., Bjarkam C. R.

Acta Neurobiologiae Experimentalis

2010

tom 70

nr 3

We aim to induce direct viral mediated gene transfer in the substantia nigra (SN) of the Göttingen minipig using MRI guided stereotaxic injections of lentiviral vectors encoding enhanced green fluorescent protein (EGFP). Nine female Göttingen minipigs were injected unilaterally into the SN with 6×2.5 μl lentivirus capable of transducing cells and mediating expression of recombinant EGFP. The animals were euthanized after four (n=3) or twenty weeks (n=6). Fresh brain tissue from three animals was used for PCR. The remaining six brains were cryo- or paraffin-sectioned for fluorescence, Nissl-, and immunohistochemical EGFP visualization. EGFP was seen in nigral neurons, axons, glial cells, endothelial cells, and in nigral fibers targeting the striatum. PCR-based detection confirmed the presence of the transgene in SN, whereas all other examined brain areas were negative, indicating that the immunohistochemically detected EGFP in the striatum derived from transfected nigral cells.

Ograniczanie wyników

2 Acta Neurobiologiae Experimentalis

2 Bendixen C.

2 Bjarkam C. R.

2 Glud A. N.

2 Hedegaard C.

2 Jensen P. H.

2 Larsen K.

2 Nielsen M. S.

2 Sorensen J. C.

1 Mogensen P. H.

1 2011

1 2010

Wyniki wyszukiwania

Direct MRI-guided stereotaxic viral mediated gene transfer of alpha-synuclein in the Gottingen minipig CNS

Direct gene transfer in the Göttingen minipig CNS using stereotaxic lentiviral microinjections