Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth 6150, Australia.
Perron Institute for Neurological and Translational Science, University of Western Australia, Perth 6009, Australia.
Int J Mol Sci. 2020 Oct 1;21(19):7282. doi: 10.3390/ijms21197282.
Parkin-type autosomal recessive juvenile-onset Parkinson's disease is caused by mutations in the gene and accounts for 50% of all autosomal recessive Parkinsonism cases. Parkin is a neuroprotective protein that has dual functions as an E3 ligase in the ubiquitin-proteasome system and as a transcriptional repressor of . While genomic deletions of exon 3 disrupt the mRNA reading frame and result in the loss of functional parkin protein, deletions of both exon 3 and 4 maintain the reading frame and are associated with a later onset, milder disease progression, indicating this particular isoform retains some function. Here, we describe in vitro evaluation of antisense oligomers that restore functional parkin expression in cells derived from a Parkinson's patient carrying a heterozygous exon 3 deletion, by inducing exon 4 skipping to correct the reading frame. We show that the induced transcript is translated into a shorter but semi-functional parkin isoform able to be recruited to depolarised mitochondria, and also transcriptionally represses expression. These results support the potential use of antisense oligomers as a disease-modifying treatment for selected pathogenic mutations.
Parkin 型常染色体隐性少年型帕金森病是由 基因突变引起的，占所有常染色体隐性帕金森病病例的 50%。Parkin 是一种神经保护蛋白，具有泛素蛋白酶体系统中 E3 连接酶和 的转录抑制剂的双重功能。虽然 外显子 3 的基因组缺失破坏了 mRNA 的阅读框，导致功能性 Parkin 蛋白丢失，但外显子 3 和 4 的缺失保持了阅读框，并与发病较晚、疾病进展较轻相关，表明这种特殊的异构体保留了一些功能。在这里，我们描述了体外评估反义寡核苷酸的结果，这些寡核苷酸通过诱导外显子 4 跳跃来纠正阅读框，从而恢复携带杂合 外显子 3 缺失的帕金森病患者来源细胞中的功能性 Parkin 表达。我们表明，诱导的 转录本被翻译成较短但半功能的 Parkin 异构体，能够被募集到去极化的线粒体，并抑制 的转录表达。这些结果支持将反义寡核苷酸作为一种有潜力的疾病修饰治疗方法，用于治疗特定的致病性 突变。
