Inherited prion diseases are linked to insertional and point mutations in the prion protein (PrP) gene, which favor conversion of PrP into a conformationally altered, pathogenic isoform. The cellular mechanism by which this process causes neurological dysfunction is unknown. Transgenic (Tg) (PG14) mice express a mouse PrP homolog of a nine-octapeptide insertion associated with an inherited prion disorder. These mice develop a progressive neurological syndrome characterized by ataxia and cerebellar atrophy due to synaptic degeneration in the molecular layer and massive apoptosis of granule neurons. To investigate the molecular events that may contribute to neurological dysfunction, we carried out a differential proteomic analysis of cerebella from Tg(PG14) mice at the preclinical, onset, and symptomatic phases of their neurological illness. 2-D maps of cerebellar proteins from Tg(PG14) mice were compared to those obtained from age-matched Tg(WT) mice that express wild-type PrP and remain healthy. Proteins whose levels were significantly modified in at least one stage of the Tg(PG14) disease were identified by PMF. Analysis detected a preclinical decrease of the calcium/calmodulin-dependent phosphatase calcineurin (CaN) in granule neurons, suggesting that dysregulation of CaN activity induced by mutant PrP may be responsible for the cerebellar dysfunction in Tg(PG14) mice.

中文翻译：

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遗传性朊病毒病转基因小鼠模型中的小脑蛋白质组分析揭示了钙调神经磷酸酶活性的临床前改变。

遗传性朊病毒疾病与朊病毒蛋白 (PrP) 基因中的插入突变和点突变有关，这有利于 PrP 转化为构象改变的致病同种型。这一过程导致神经功能障碍的细胞机制尚不清楚。转基因 (Tg) (PG14) 小鼠表达与遗传性朊病毒疾病相关的九八肽插入的小鼠 PrP 同源物。由于分子层的突触变性和颗粒神经元的大量凋亡，这些小鼠发展出一种以共济失调和小脑萎缩为特征的进行性神经系统综合征。为了研究可能导致神经功能障碍的分子事件，我们对 Tg(PG14) 小鼠在其神经疾病的临床前、发病和症状阶段的小脑进行了差异蛋白质组学分析。将 Tg(PG14) 小鼠的小脑蛋白的二维图与从表达野生型 PrP 并保持健康的年龄匹配的 Tg(WT) 小鼠获得的那些进行了比较。PMF 鉴定了在 Tg(PG14) 疾病的至少一个阶段中其水平显着改变的蛋白质。分析检测到颗粒神经元中钙/钙调蛋白依赖性磷酸酶钙调神经磷酸酶 (CaN) 的临床前减少，这表明突变 PrP 诱导的 CaN 活性失调可能是 Tg(PG14) 小鼠小脑功能障碍的原因。