An abnormal protein interaction that led to nerve fiber degeneration in a mouse model of Charcot-Marie-Tooth (CMT) disease type 2D may suggest a new approach to developing treatments for this disease subtype.
The study, “Aberrant GlyRS-HDAC6 interaction links to axonal transport deficit in Charcot-Marie-Tooth neuropathy,” appeared in the journal Nature Communications.
CMT2D is caused by mutations in the GARS gene, which provides instructions to make the protein GlyRS. Although GlyRS is produced by all cells in the body, patients with CMT2D only show symptoms in the arms and legs, particularly in the hands and feet.
Previous research showed an abnormal interaction between GlyRS and a protein called neuropilin 1 (Nrp1), which has also been associated with motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis (ALS). However, the link between mutant GlyRS and degeneration of axons, or nerve fibers, requires more research.
A team at The Scripps Research Institute found that mutant GlyRS proteins interact abnormally with HDAC6 in mice. The HDAC6 protein is involved in a process called acetylation and regulates gene expression. Acetylation readies a cellular protein called alpha-tubulin for its role in forming microtubules, which help to transport signaling proteins and other important molecules.
Abnormal GlyRS-HDAC6 interaction led to deacetylation — the removal of acetyl chemical groups — of alpha-tubulin, which impaired the transport of nervous system signals prior to CMT2D onset in mice. The disruption is more evident in longer nerves, which explains why hands and feet are affected more severely.
Results also showed that using an HDAC6 blocker to restore alpha-tubulin acetylation repaired nerve fiber transport, and improved motor function in mouse models of CMT2D.
“These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target,” the researchers said.
Besides proving the benefit of studying the root causes of CMT, the research suggests that a molecule similar to the HDAC6 inhibitor could be a promising treatment strategy, the investigators said.
“It’s exciting when you can accumulate all the evidence and point to a specific target,” Zhongying Mo, PhD, the study’s first author, said in a press release.
Ultimately, the researchers aim to treat all types of CMT. This is a challenging goal because mutations greatly vary from patient to patient, leading to a wide variety of symptoms. “That variability is striking,” said Xiang-Lei Yang, PhD, the study’s senior author.
Researchers now plan to study other abnormal protein interactions linked with CMT and find a way to correct them.
“Our understanding of the disease is ever-increasing,” Yang said.