Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy

Zhongying Mo, Xiaobei Zhao, Huaqing Liu, Qinghua Hu, Xu-Qiao Chen, Jessica Pham, Na Wei, Ze Liu, Jiadong Zhou, Robert W. Burgess, Samuel L. Pfaff, C. Thomas Caskey, Chengbiao Wu, Ge Bai and Xiang-Lei Yang ()
Additional contact information
Zhongying Mo: The Scripps Research Institute
Xiaobei Zhao: University of California at San Diego
Huaqing Liu: The Scripps Research Institute
Qinghua Hu: The Scripps Research Institute
Xu-Qiao Chen: University of California at San Diego
Jessica Pham: The Scripps Research Institute
Na Wei: The Scripps Research Institute
Ze Liu: The Scripps Research Institute
Jiadong Zhou: The Scripps Research Institute
Robert W. Burgess: The Jackson Laboratory
Samuel L. Pfaff: The Salk Institute for Biological Studies
C. Thomas Caskey: Baylor College of Medicine
Chengbiao Wu: University of California at San Diego
Ge Bai: The Scripps Research Institute
Xiang-Lei Yang: The Scripps Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease’s specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset. An HDAC6 inhibitor used to restore α-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice. These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target. Moreover, the HDAC6 interaction differs from Nrp1 interaction among GlyRS mutants and correlates with divergent clinical presentations, indicating the existence of multiple and different mechanisms in CMT2D.

Date: 2018
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-018-03461-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03461-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-03461-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().