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PMID:28108290

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Citation

Lee, JS, Chang, EH, Koo, OJ, Jwa, DH, Mo, WM, Kwak, G, Moon, HW, Park, HT, Hong, YB and Choi, BO (2017) Pmp22 mutant allele-specific siRNA alleviates demyelinating neuropathic phenotype in vivo. Neurobiol. Dis. 100:99-107

Abstract

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.

Links

PubMed Online version:10.1016/j.nbd.2017.01.006

Keywords

Alleles; Animals; Charcot-Marie-Tooth Disease/genetics; Charcot-Marie-Tooth Disease/pathology; Demyelinating Diseases/genetics; Demyelinating Diseases/pathology; Mice, Transgenic; Mutation/genetics; Myelin Proteins/genetics; Phenotype; RNA, Small Interfering/genetics; Schwann Cells/metabolism; Sciatic Nerve/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PMP22

enables

GO:0003774: cytoskeletal motor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0055001: muscle cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0019226: transmission of nerve impulse

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0042552: myelination

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0048747: muscle fiber development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PMP22

enables

GO:0003774: motor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0010468: regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0014037: Schwann cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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