SUMMARY:
The readthrough molecules associated to NMD inhibitors for the treatment of genetic alterations in CMT, opening the way for future investigations and a potential therapy.
TITLE:
Amlexanox: Readthrough Induction and Nonsense-Mediated mRNA Decay Inhibition in a Charcot-Marie-Tooth Model of hiPSCs-Derived Neuronal Cells Harboring a Nonsense Mutation in GDAP1 Gene
DESCRIPTION:
Nonsense mutations are involved in multiple peripheral neuropathies. These mutations induce the presence of a premature termination codon (PTC) at the mRNA level. As a result, a dysfunctional or truncated protein is synthesized, or even absent linked to nonsense-mediated mRNA degradation (NMD) system activation. Readthrough molecules or NMD inhibitors could be innovative therapies in these hereditary neuropathies, particularly molecules harboring the dual activity as amlexanox….
CONTENT:
Pharmaceuticals (Basel). 2023 Jul 21;16(7):1034. doi: 10.3390/ph16071034.
ABSTRACT
Nonsense mutations are involved in multiple peripheral neuropathies. These mutations induce the presence of a premature termination codon (PTC) at the mRNA level. As a result, a dysfunctional or truncated protein is synthesized, or even absent linked to nonsense-mediated mRNA degradation (NMD) system activation. Readthrough molecules or NMD inhibitors could be innovative therapies in these hereditary neuropathies, particularly molecules harboring the dual activity as amlexanox. Charcot-Marie-Tooth (CMT) is the most common inherited pathology of the peripheral nervous system, affecting 1 in 2500 people worldwide. Nonsense mutations in the GDAP1 gene have been associated with a severe form of CMT, prompting us to investigate the effect of readthrough and NMD inhibitor molecules. Although not clearly defined, GDAP1 could be involved in mitochondrial functions, such as mitophagy. We focused on the homozygous c.581C>G (p.Ser194*) mutation inducing CMT2H using patient human induced pluripotent stem cell (hiPSC)-derived neuronal cells. Treatment during 20 h with 100 µM of amlexanox on this cell model stabilized GDAP1 mRNAs carrying UGA-PTC and induced a restoration of the mitochondrial morphology. These results highlight the potential of readthrough molecules associated to NMD inhibitors for the treatment of genetic alterations in CMT, opening the way for future investigations and a potential therapy.
PMID:37513945 | DOI:10.3390/ph16071034
SOURCE:
Pharmaceuticals (Basel, Switzerland)
TAGS:
NMD inhibitors
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2023-07-24T06:14:56Z
DATE – DOI: 2023-07-24T06:14:56Z
DATE – PUBMED: 2023 Jul 21
DATE OUTPUT MATCHED: True
DATE – ADDED:
Sat, 29 Jul 2023 06:00:00 -0400
DATE – RETRIEVED:
07/29/23 11:51AM
2023-07-29T11:51:23-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:37513945,doi:10.3390/ph16071034
PUBMED ID:
pubmed:37513945
DOI:
10.3390/ph16071034
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/37513945/
LINK – DOI:
https://doi.org/10.3390/ph16071034
LINK – PUBLISHER:
https://www.mdpi.com/1424-8247/16/7/1034
REFERENCES:
CMT Treatment Report, Urgent Research, 2023-07-29T11:51:23-04:00, https://www.cmttreatmentreport.com.
