Peripherin Is a Subunit of Peripheral Nerve Neurofilaments: Implications for Differential Vulnerability of CNS and Peripheral Nervous System Axons
Peripherin Is a Subunit of Peripheral Nerve Neurofilaments: Implications for Differential Vulnerability of CNS and Peripheral Nervous System Axons
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DOI：
10.1523/jneurosci.1081-12.2012
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发表时间：
2012-06-20
影响因子：
5.3
通讯作者：
Nixon, Ralph A.
中科院分区：
文献类型：
--
作者：
Yuan, Aidong;Sasaki, Takahiro;Nixon, Ralph A.
Peripherin是一种与神经退行性疾病有关的神经元中间丝蛋白，与神经丝三联体蛋白[神经丝轻链（NFL）、中链（NFM）和重链（NFH）]共存，但功能未知。外周蛋白在脑发育过程中比三联体更早的峰值表达及其形成均聚物的能力，与专性杂聚物的三联体不同，支持了广泛持有的观点，即外周蛋白和神经丝三联体形成单独的丝系统。然而，在这里，我们证明，尽管出生后的表达下降，外周蛋白是丰富的三重在成人PNS和存在于一个相对固定的化学计量与这些亚基。Peripherin表现出相同的分布模式的三联体蛋白在坐骨神经轴突和共定位与NFL单神经丝通过免疫金电子显微镜。在四重或五重转染的SW 13 vim（-）细胞中，外周蛋白还共组装成含有NFL、NFM和NFH的单个细丝网络，其中含有和不含α-内连接蛋白。在小鼠中基因删除NFL显著降低了坐骨神经轴突中的外周蛋白含量。此外，外周蛋白突变已被证明会破坏转染SW 13 vim（-）细胞中的神经丝网络。这些数据表明外周蛋白和神经丝蛋白在功能上是相互依赖的。结果强烈支持这样的观点，而不是形成一个独立的结构，外周蛋白是一个亚单位的神经丝在成人PNS。我们的研究结果提供了一个基础，它与神经丝在PNS疾病与神经丝积累的密切关系。
Peripherin, a neuronal intermediate filament protein implicated in neurodegenerative disease, coexists with the neurofilament triplet proteins [neurofilament light (NFL), medium (NFM), and heavy (NFH) chain] but has an unknown function. The earlier peak expression of peripherin than the triplet during brain development and its ability to form homopolymers, unlike the triplet, which are obligate heteropolymers, have supported a widely held view that peripherin and neurofilament triplets form separate filament systems. However, here, we demonstrate that, despite a postnatal decline in expression, peripherin is as abundant as the triplet in the adult PNS and exists in a relatively fixed stoichiometry with these subunits. Peripherin exhibits a distribution pattern identical to those of triplet proteins in sciatic axons and colocalizes with NFL on single neurofilaments by immunogold electron microscopy. Peripherin also coassembles into a single network of filaments containing NFL, NFM, and NFH with and without alpha-internexin in quadruple- or quintuple-transfected SW13vim(-) cells. Genetically deleting NFL in mice dramatically reduces peripherin content in sciatic axons. Moreover, peripherin mutations has been shown to disrupt the neurofilament network in transfected SW13vim(-) cells. These data show that peripherin and the neurofilament proteins are functionally interdependent. The results strongly support the view that, rather than forming an independent structure, peripherin is a subunit of neurofilaments in the adult PNS. Our findings provide a basis for its close relationship with neurofilaments in PNS diseases associated with neurofilament accumulation.