SUMMARY:
BDNF-boosting therapies could represent a viable therapeutic strategy for CMT2D.
TITLE:
Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice
DESCRIPTION:
Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterising Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor TrkB, underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete. Through intravital…
CONTENT:
JCI Insight. 2023 Mar 16:e157191. doi: 10.1172/jci.insight.157191. Online ahead of print.
ABSTRACT
Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterising Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor TrkB, underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete. Through intravital imaging of the sciatic nerve, we show that CMT2D mice display early and persistent disturbances in axonal transport of neurotrophin-containing signalling endosomes in vivo. We discovered that BDNF-TrkB impairments correlate with transport disruption and overall CMT2D neuropathology, and that inhibition of this pathway at the nerve-muscle interface perturbs endosome transport in wild-type axons. Accordingly, supplementation of muscles with BDNF, but not other neurotrophins, completely restores physiological axonal transport in neuropathic mice. Together, these findings suggest that selectively targeting muscles with BDNF-boosting therapies could represent a viable therapeutic strategy for CMT2D.
PMID:36928301 | DOI:10.1172/jci.insight.157191
SOURCE:
JCI insight
TAGS:
BDNF
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2023-03-16T16:00:44Z
DATE – DOI: 2023-03-16T16:00:44Z
DATE – PUBMED: 2023 Mar 16
DATE OUTPUT MATCHED: True
DATE – ADDED:
Fri, 17 Mar 2023 06:00:00 -0400
DATE – RETRIEVED:
03/17/23 01:02PM
2023-03-17T13:02:52-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:36928301,doi:10.1172/jci.insight.157191
PUBMED ID:
pubmed:36928301
DOI:
10.1172/jci.insight.157191
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36928301/
LINK – DOI:
https://doi.org/10.1172/jci.insight.157191
LINK – PUBLISHER:
http://insight.jci.org/articles/view/157191
REFERENCES:
CMT Treatment Report, Urgent Research, 2023-03-17T13:02:52-04:00, https://www.cmttreatmentreport.com.
