amyotrophic lateral sclerosis (ALS), commonly known as gradual freezing, is a progressive paralytic disease characterized by degenerative changes in the cerebral motor cortex, brain stem and spinal cord motor neurons. Its clinical manifestations are mainly gradual Exacerbated muscle weakness, atrophy, fasciculation , bulbar palsy and vertebral body damage, eventually leading to difficulty swallowing, respiratory muscle weakness and death. The core pathological changes of ALS are motor cortex and spinal cord motor neuron apoptosis, accompanied by a neuroinflammatory response of astrocytes, microglia and oligodendrocyte proliferation. Another typical pathological feature of ALS is the degeneration and loss of function of the neuromuscular junction between the descending motor neurons of the spinal cord and peripheral muscles, as well as the atrophy and spasm of the peripheral muscle system.
Global epidemiological surveys show that the number of new cases of ALS per 100,000 people each year is 1-2 cases, and the incidence and prevalence increase with age. About 10% of ALS is inherited in the family Sex, the rest are sporadic. The research on ALS pathogenic genes and pathogenic mechanisms has always been a research hotspot in this field. Since the first ALS pathogenic gene SOD1 was reported, a total of nearly 50 genes have been reported successively, and their mutations/dysfunctions have participated in or affected the occurrence and development of ALS, including TDP43, FUS, C9orf72, HNRNPA1, SQSTM1 VCP, OPTN, PFN, CHCHD2 and CHCHD10, etc. These genes are widely involved in the regulation of intracellular protein stability, RNA metabolism and stability, and cytoskeleton dynamic changes. Among them, TDP43, FUS, C9orf72 and SOD1 gene mutations cause about 70% of the occurrence of family inherited ALS. The pathological cause of TDP43 and SOD1 pathogenic 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. The translocation of TDP43 from the nucleus to the cytoplasm and the accumulation of protein aggregates is a typical feature of hereditary and sporadic ALS, and is often regarded as one of the signs of ALS diseased motor neurons.
RNF220 is a new ubiquitin ligase identified by Mao Bingyu's team, a researcher at the Kunming Institute of Zoology, Chinese Academy of Sciences, which plays an important role in the development of the nervous system. Early research by the team found that the ubiquitin ligase RNF220 is involved in the regulation of multiple nervous system development processes by regulating different types of ubiquitination modifications of different target proteins. Although RNF220-/- mice were born and lethal, about 1/3 of RNF220+/- mice showed progressive dyskinesia as adults, and finally died of paralysis. Behavioral analysis of open field and rotating rod found that the exercise ability of RNF220+/- mice was significantly reduced. Through tissue section and pathological staining analysis, it is found that RNF220 is specifically expressed in spinal cord motor neurons of adult mice, and its protein is mainly located in the cytoplasm; compared with wild-type mice, RNF220+/- mouse spinal cord motor neurons The TDP43 protein in the metacytes showed a translocation from the nucleus to the cytoplasm and increased protein levels; the diameter of gastrocnemius muscle fibers in RNF220+/- mice became smaller, showing atrophy and denervation of the muscles. Therefore, RNF220+/- mice exhibit behavior and pathological characteristics similar to human ALS. In vivo and in vitro biochemical analysis found that RNF220 participates in the regulation of TDP43 protein stability by promoting the classical ubiquitination modification of TDP43 protein K48.
This study reveals a new mechanism of ALS-related protein TDP43 stability regulation, enriches people's understanding of the mechanism of ALS, and provides new potential targets and animal model support for the diagnosis and treatment of ALS. Recently, the research results were published in Journal of Molecular Cell Biologyz3 under the title Haploinsufficiency of the TDP43 ubiquitin E3 ligase RNF220 leads to ALS-like motor neuron defects in mousez32 on. Associate researcher Ma Pengcheng of Kunming Institute of Zoology and PhD student Li Yuwei are the co-first authors of the article, and Mao Bingyu is the corresponding author of the article. This research is supported by the National Natural Science Foundation of China and the key projects of Yunnan Province.
RNF220 regulates the stability of spinal motor neuron TDP43 protein and the occurrence and development of ALS
Source: Kunming Institute of Zoology, Chinese Academy of Sciences
