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Marusela?Oliveras-Salvá Anke?Van der Perren Nicolas?Casadei Stijn?Stroobants Silke?Nuber Rudi?D’Hooge Chris?Van den Haute Veerle?BaekelandtEmail author 《Molecular neurodegeneration》2013,8(1):44
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 rAAV2/7.3.
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L. Verdoodt A. Van Haute I. J. Goderis K. De Witte J. Keulemans W. Broothaerts 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》1998,96(2):294-300
To obtain homozygous genotypes of apple, we have induced haploid development of either the female or the male gametes by
parthenogenesis in situ and anther culture, respectively. Of the shoots obtained, which were mainly of a non-haploid nature,
some could be derived from fertilised egg cells or from sporophytic anther tissue. In order to select the shoots having a
true haploid origin, and thus homozygotes, we decided to use the single multi-allelic self-incompatibility gene as a molecular
marker to discriminate homozygous from heterozygous individuals. The rationale behind this approach was that diploid apple
cultivars contain 2 different alleles of the S-gene and therefore the haploid induced shoots obtained from them should have only one of the alleles of the single parent.
The parental cultivars used were ‘Idared’ (parthenogenesis in situ) and ‘Braeburn’ (androgenesis), and their S-genotypes were known, except for 1 of the ‘Braeburn’S-alleles. To stimulate parthenogenetic development ‘Idared’ styles were pollinated with irradiated ‘Baskatong’ pollen, the
S-alleles of the latter (2n) cultivar were also unknown. The cloning and sequence analysis of these 3 unidentified S-alleles, 1 from ‘Braeburn’ and 2 from ‘Baskatong’ is described, and we show that they correspond to the S
24
-, S
26
- and S
27
-alleles. We have optimised a method for analysis of the S-alleles of ‘Idared/Baskatong’- or ‘Braeburn’-derived in vitro plant tissues and have shown that this approach can be applied
for the screening of the in vitro shoots for their haploid origin.
Received: 18 August 1997 / Accepted: 10 September 1997 相似文献
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I. Van Nerum M. Geerts A. Van Haute J. Keulemans W. Broothaerts 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2001,103(4):584-591
Recently, the self-incompatibility (S-) genotypes of 56 apple cultivars were examined by protein analysis, which led to the
identification by Boskovic and Tobutt of 14 putative ’new’ S-alleles, S12 to S25. This paper reports a re-examination of the
S-genotypes of some of these cultivars through S-allele ’specific’ PCR and sequence analysis. The results obtained by this
analysis indicated that the number of S-alleles that are present in apple is probably smaller than the number proposed by
Boskovic and Tobutt. The existence of three ’new’ S-alleles (S20, S22 and S24) was confirmed. The existence of two other putative
’new’ S-alleles (S23 and S25) was, however, contradicted. The coding sequences of the S-alleles that correspond to the S10
and the S25 ribonuclease bands as well as those corresponding to the S22 and the S23 ribonuclease bands were shown to be identical
in sequence. Interestingly, the S-allele corresponding to the S22 and the S23 ribonuclease bands shared a high sequence identity
(99% identity) with S27, which was previously cloned and sequenced from Baskatong, but which was not included in the analysis
conducted by Boskovic and Tobutt. Both S-alleles only differ in point mutations, which are not translated into differences
in amino-acid sequence. To our knowledge, this is the first report of two S-alleles that differ at the nucleotide level but
still encode for identical S-RNases. The implications of these observations for determining the S-genotypes of plants by PCR
analysis or protein analysis are discussed.
Received: 10 January 2001 / Accepted: 19 January 2001 相似文献
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The warm-season perennial switchgrass (Panicum virgatum) is a candidate bioenergy crop. To be successful, switchgrass production must be maintained on low-quality landscapes with minimal inputs while facing future climates that are expected to be more extreme and more variable. We propose that antecedent rainfall constrains how plants respond to drought, as well as subsequently recover from drought. To test this idea, we examined how six switchgrass genotypes responded to a 1-year severe drought and then recovered under normal rainfall in the following year. These plants had previously grown for 3 years under a range of dry to wet rainfall levels in a shallow-soil common garden with no fertilizer. Plants previously exposed to drought produced less biomass, and basal area after the severe drought was relieved compared to previously well-watered plants. In addition, there were legacy effects caused by plant size: plants that were larger pre-drought were more likely to survive the severe drought, and plants that were larger during the severe drought recovered more biomass, basal area, and tillers post-drought. Although genotypes differed somewhat in their responses, the size constraint was consistent across genotypes. These findings suggest that we can establish more drought-resilient switchgrass stands by, for example, planning for initial irrigation or planting during a wet year to allow plants to grow larger prior to experiencing drought. Additional studies are needed to understand whether these rainfall and size legacies persist or are transient. 相似文献
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