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首页> 外文期刊>The European Journal of Neuroscience >Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein.
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Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein.

机译：表达α-突触核蛋白的A30P突变体形式的小鼠的成年嗅球神经发生变化。

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摘要

In familial and sporadic forms of Parkinson's disease (PD), alpha-synuclein pathology is present in the brain stem nuclei and olfactory bulb (OB) long before Lewy bodies are detected in the substantia nigra. The OB is an active region of adult neurogenesis, where newly generated neurons physiologically integrate. While accumulation of wild-type alpha-synuclein is one of the pathogenic hallmarks of non-genetic forms of PD, the A30P alpha-synuclein mutation results in an earlier disease onset and a severe clinical phenotype. Here, we study the regulation of adult neurogenesis in the subventricular zone (SVZ)/OB system in a tetracycline-suppressive (tet-off) transgenic model of synucleinopathies, expressing human mutant A30P alpha-synuclein under the control of the calcium/calmodulin-dependent protein kinase II alpha (CaMK) promoter. In A30P transgenic mice alpha-synuclein was abundant at the site of integration in the glomerular cell layer of the OB. Without changes in proliferation in the SVZ, significantly fewer newly generated neurons were observed in the OB granule cell and glomerular layers of A30P transgenic mice than in controls, most probably due to increased cell death. By tetracycline-dependent abrogation of A30P alpha-synuclein expression, OB neurogenesis and programmed cell death was restored to control levels. Our results indicate that, using A30P conditional (tet-off) mice, A30P alpha-synuclein has a negative impact on olfactory neurogenesis and suppression of A30P alpha-synuclein enhances survival of newly generated neurons. This finding suggests that interfering with alpha-synuclein pathology can rescue newly generated neurons, possibly leading to new targets for therapeutic interventions in synucleinopathies.
机译：在帕金森氏病（PD）的家族性和散发性形式中，早在黑质中检测到路易体之前，脑干细胞核和嗅球（OB）中就存在α-突触核蛋白病理。 OB是成人神经发生的活跃区域，在这里新生成的神经元在生理上整合。虽然野生型α-突触核蛋白的积累是PD非遗传形式的致病标志之一，但A30Pα-突触核蛋白突变导致疾病发作更早，并且临床表现更为严重。在这里，我们研究了突触核蛋白病的四环素抑制（tet-off）转基因模型在脑室下区域（SVZ）/ OB系统中对成年神经发生的调控，该模型在钙/钙调蛋白-控制下表达人突变体A30Pα-突触核蛋白。依赖性蛋白激酶IIα（CaMK）启动子。在A30P转基因小鼠中，α-突触核蛋白在OB的肾小球细胞层的整合位点丰富。在SVZ中增殖没有变化的情况下，与对照组相比，在A30P转基因小鼠的OB颗粒细胞和肾小球层中观察到的新生成的神经元明显减少，这很可能是由于细胞死亡增加所致。通过四环素依赖的A30Pα-突触核蛋白表达的废除，OB神经发生和程序性细胞死亡恢复到控制水平。我们的结果表明，使用A30P有条件的（tet-off）小鼠，A30Pα-突触核蛋白对嗅觉神经发生有负面影响，而A30Pα-突触核蛋白的抑制可增强新生神经元的存活。该发现表明，干扰α-突触核蛋白的病理学可以拯救新产生的神经元，可能导致突触核蛋白病的治疗干预的新靶标。

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