Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Ann Neurol. 2012 Feb;71(2):245-57. doi: 10.1002/ana.22598.
Huntington disease-like 2 (HDL2) is a progressive, late onset autosomal dominant neurodegenerative disorder, with remarkable similarities to Huntington disease (HD). HDL2 is caused by a CTG/CAG repeat expansion. In the CTG orientation, the repeat is located within the alternatively spliced exon 2A of junctophilin-3 (JPH3), potentially encoding polyleucine and polyalanine, whereas on the strand antisense to JPH3, the repeat is in frame to encode polyglutamine. The JPH3 protein product serves to stabilize junctional membrane complexes and regulate neuronal calcium flux. We have previously demonstrated the potential pathogenic properties of JPH3 transcripts containing expanded CUG repeats. The aim of this study was to test the possibility that loss of JPH3 expression or expanded amino acid tracts also contribute to HDL2 pathogenesis.
Transcripts from the HDL2 locus, and their protein products, were examined in HDL2, HD, and control frontal cortex. The effect of loss of Jph3 was examined in mice with partial or complete loss of Jph3.
Bidirectional transcription occurs at the HDL2 locus, although expression of antisense transcripts with expanded CAG repeats is limited. Protein products with expanded amino acid tracts were not detected in HDL2 brain. However, JPH3 transcripts and full-length JPH3 protein are decreased in HDL2 brain, and Jph3 hemizygous and null mice exhibit abnormal motor function.
Our results suggest that the pathogenic mechanism of HDL2 is multifactorial, involving both a toxic gain of function of JPH3 RNA and a toxic loss of JPH3 expression.
亨廷顿病样 2 型（HDL2）是一种进行性、迟发性常染色体显性神经退行性疾病，与亨廷顿病（HD）有显著相似之处。HDL2 是由 CTG/CAG 重复扩展引起的。在 CTG 方向上，重复位于连接蛋白 3（JPH3）的选择性剪接外显子 2A 内，可能编码多亮氨酸和多丙氨酸，而在与 JPH3 反义的链上，重复与编码多谷氨酰胺的框内。JPH3 蛋白产物有助于稳定连接膜复合物并调节神经元钙流。我们之前已经证明了含有扩展 CUG 重复的 JPH3 转录本的潜在致病特性。本研究的目的是检验 JPH3 表达缺失或扩展的氨基酸片段是否也导致 HDL2 发病的可能性。
在 HDL2、HD 和对照额皮质中检查 HDL2 基因座的转录本及其蛋白质产物。在 Jph3 部分或完全缺失的小鼠中，检查 Jph3 缺失的影响。
在 HDL2 基因座上发生双向转录，尽管表达具有扩展 CAG 重复的反义转录本受到限制。在 HDL2 大脑中未检测到具有扩展氨基酸片段的蛋白质产物。然而，JPH3 转录本和全长 JPH3 蛋白在 HDL2 大脑中减少，Jph3 半合子和纯合子小鼠表现出异常的运动功能。
我们的结果表明，HDL2 的致病机制是多因素的，既涉及 JPH3 RNA 的毒性获得功能，也涉及 JPH3 表达的毒性丧失。
