A new mechanism for regulating the stability of amyotrophic lateral sclerosis associated protein Tdp43

Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disease characterized by degenerative changes of motor neurons in the brain motor cortex, brain stem and spinal cord.

The core pathological change of ALS is the apoptosis of motor neurons in motor cortex and spinal cord, accompanied by the neuroinflammatory reaction of astrocyte, microglia and oligodendrocyte proliferation.

Another typical pathological feature of ALS is degeneration and dysfunction of neuromuscular junction of descending motor neurons and peripheral muscles in spinal cord, and atrophy and spasm of peripheral muscle system.

According to the survey

Epidemiological survey worldwide showed that 1-2 new cases of ALS occurred annually in every 100 thousand people, and the incidence rate and prevalence rate increased with age.

About 10% of ALS was familial and the rest was sporadic.
Since SOD1, the first pathogenic gene of ALS, was reported, nearly 50 genes have been reported one after another.

The mutations / dysfunction of SOD1 play an important role in the occurrence and development of ALS, including tdp43, Fus, c9orf72, hnRNPA1, sqstm1, VCP, OPTN, PFN, chchd2 and chchd10.

These genes are widely involved in the regulation of intracellular protein stability, RNA metabolism and stability, and the dynamic changes of cytoskeleton.

Mutations in tdp43, Fus, c9orf72 and SOD1 genes lead to about 70% of familial ALS.

The pathological cause of tdp43 and SOD1 mutations is neurotoxicity caused by abnormal accumulation of mutant proteins in motor neuron cell bodies.

Under normal physiological conditions, tdp43 is mainly located in the nucleus of motor neurons and participates in the regulation of RNA metabolism.

Tdp43 translocation from nucleus to cytoplasm and accumulation of protein aggregates are typical characteristics of hereditary and sporadic ALS, and are often considered as one of the markers of motor neurons in ALS lesions.

Rnf220 is a new ubiquitin ligase identified by Mao Bingyu, a researcher of Kunming Institute of zoology, Chinese Academy of Sciences.

It plays an important role in the development of nervous system. The team’s early research found that the ubiquitin ligase rnf220 is involved in the regulation of multiple nervous system development processes by regulating different types of ubiquitination of different target proteins.

Although rnf220 – / – mice died at birth, about one third of rnf220 + / – mice showed progressive dyskinesia and eventually died of paralysis.

Behavioral analysis of open field and stick rotation showed that the motor ability of rnf220 + / – mice was significantly decreased.

The results of histological and pathological analysis showed that rnf220 was specifically expressed in adult mouse spinal motoneurons, and its protein was mainly located in the cytoplasm.

compared with wild-type mice, tdp43 protein in rnf220 + / – mice spinal motoneurons showed a phenomenon of translocation from nucleus to cytoplasm, and the protein level was increased.

The expression of tdp43 protein in rnf220 + / – mice spinal motoneurons was higher than that in wild-type mice The diameter of the fibers became smaller, showing atrophy and muscle denervation.

Therefore, rnf220 + / – mice showed similar behavioral and pathological characteristics to human ALS. In vivo and in vitro biochemical analysis showed that rnf220 was involved in the regulation of tdp43 protein stability by promoting the classical ubiquitination of K48 type of tdp43 protein.

This study revealed a new mechanism of stability regulation of ALS related protein tdp43, enriched people’s understanding of the pathogenesis of ALS, and provided a new potential target and animal model support for the diagnosis and treatment of ALS.

Recently, the research results were published in the Journal of molecular cell biology with the title of haploinsufficiency of the tdp43 ubiquitin E3 ligase rnf220 leads to ALS like motor neuron defects in mouse.

Ma Pengcheng, an associate researcher of Kunming Institute of zoology, and Li Yuwei, a doctoral student, are the co first authors of the article, and Mao Bingyu is the corresponding author of the article.

The research work is supported by the National Natural Science Foundation of China and key projects of Yunnan Province.