Researchers found that HERC1 protein may be important for the production of myelin, the protective layer in peripheral nerves.
This discovery, from a mouse study, increases scientific knowledge about the processes involved in several demyelinating disorders, including Charcot-Marie-Tooth (CMT) disease.
The study, “HERC1 Ubiquitin Ligase Is Required for Normal Axonal Myelination in the Peripheral Nervous System,” was published in the journal Molecular Neurobiology.
HERC1 protein is involved in the ubiquitin-proteasome system (UPS), which is critical for proper protein degradation and healthy nerve cells.
Alterations to this system have been linked to the development of several neurodegenerative disorders, including severe forms of CMT, spinal muscular atrophy (SMA), and amyotrophic lateral sclerosis (ALS).
The research team also evaluated the impact of HERC1 gene mutations on the progressive degeneration of peripheral nerve cells by studying the tambaleante (tbl) mutant mouse.
This mouse model shows tremors, unstable gait, abnormal posture of the back limbs, and loss of a subset of nerve cells in the brain that control movement, called Purkinje cells. All these features are caused by a single mutation in the HERC1 gene.
The mice showed a two-fold increased delay between nerve stimulation and the expected muscular response, compared to healthy mice. This could in part be explained by the abnormal localization of Schwann cells (myelin-producing cells) at the muscle-nerve connection point.
Also, abnormal myelin patterns and thicker myelin layers with signs of degeneration were detected in the nerve cells of the mice. Myelin protects nerve cells, but it is also essential for communication between these cells.
These differences were found to be regulated by one signaling pathway known as the Pi3K/Akt pathway. Tambaleante mice had about a four times higher activation of the pathway compared to healthy mice, suggesting that Pi3K/Akt takes part in HERC1 dysfunction.
The researchers believe these findings support the role of HERC1 protein in the peripheral motor nervous system, as it seems to aid normal nerve cell responsiveness.
“Our results suggest that tbl mice could be a potential disease model for peripheral neuropathies. The myelin abnormalities found in our model are [tissue] hallmarks of some CMT forms,” the researchers wrote.
“Indeed, CMT mice models present slowly progressive weakness and atrophy of the distal limb muscles, similar to that found in tbl mice,” they added.