کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5630669 1580621 2017 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Pmp22 mutant allele-specific siRNA alleviates demyelinating neuropathic phenotype in vivo
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی عصب شناسی
پیش نمایش صفحه اول مقاله
Pmp22 mutant allele-specific siRNA alleviates demyelinating neuropathic phenotype in vivo
چکیده انگلیسی


- A small interfering RNA specifically reduced the expression level of the Pmp22 mutant allele and reversed the low viability of Schwann cells.
- A Pmp22 mutant allele-specific siRNA alleviated demyelination and abnormal nerve conduction velocity in a mouse model.
- Down-regulation of Pmp22 mutant alleles increased myelinating proteins and reduced ER stress-related proteins.

Charcot-Marie-Tooth disease (CMT) is a genetic disorder that can be caused by aberrations in > 80 genes. CMT has heterogeneous modes of inheritance, including autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. Over 95% of cases are dominantly inherited. In this study, we investigated whether regulation of a mutant allele by an allele-specific small interfering RNA (siRNA) can alleviate the demyelinating neuropathic phenotype of CMT. We designed 19 different allele-specific siRNAs for Trembler J (Tr-J) mice harboring a naturally occurring mutation (Leu16Pro) in Pmp22. Using a luciferase assay, we identified an siRNA that specifically and selectively reduced the expression level of the mutant allele and reversed the low viability of Schwann cells caused by mutant Pmp22 over-expression in vitro. The in vivo efficacy of the allele-specific siRNA was assessed by its intraperitoneal injection to postnatal day 6 of Tr-J mice. Administration of the allele-specific siRNA to Tr-J mice significantly enhanced motor function and muscle volume, as assessed by the rotarod test and magnetic resonance imaging analysis, respectively. Increases in motor nerve conduction velocity and compound muscle action potentials were also observed in the treated mice. In addition, myelination, as evidenced by toluidine blue staining and electron microscopy, was augmented in the sciatic nerves of the mice after allele-specific siRNA treatment. After validating suppression of the Pmp22 mutant allele at the mRNA level in the Schwann cells of Tr-J mice, we observed increased expression levels of myelinating proteins such as myelin basic protein and myelin protein zero. These data indicate that selective suppression of the Pmp22 mutant allele by non-viral delivery of siRNA alleviates the demyelinating neuropathic phenotypes of CMT in vivo, implicating allele-specific siRNA treatment as a potent therapeutic strategy for dominantly inherited peripheral neuropathies.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neurobiology of Disease - Volume 100, April 2017, Pages 99-107
نویسندگان
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