2023/07/21
The University of Tokyo
Kanazawa University
Keio University School of Medicine
A research group, including Project Researcher Dan Li (currently a researcher at Harvard University) and Professor Makoto Nakanishi of the Division of Cancer Cell Biology at The Institute of Medical Science, The University of Tokyo; Professor Tatsushi Toda of the Graduate School of Medical Sciences at The University of Tokyo; and Professor Yoshikazu Johmura of the Cancer Research Institute at Kanazawa University, has identified a new enzyme that induces the degradation of abnormal protein aggregates within nerve cells. Although several enzymes that specifically ubiquitinate and induce the degradation of misfolded proteins were previously known, the enzymes responsible for ubiquitinating and inducing the degradation of misfolded proteins that cause neurodegenerative diseases in nerve cells were not well understood.
In this study, the group discovered that the LONRF2 enzyme selectively ubiquitinates denatured hnRNP and TDP43 proteins, which cause amyotrophic lateral sclerosis (ALS). Lonrf2 knockout mice exhibited age-dependent ALS-like symptoms, and pathological analysis revealed neurodegeneration and nerve cell death in the motor neurons of the spinal cord and cerebral cortex, thought to be caused by protein aggregates such as TDP43. The researchers also identified a variant gene that results in a complete loss of LONRF2 function in patients with sporadic ALS. Most importantly, when the Lonrf2 gene was introduced into motor neurons differentiated from iPS cells derived from ALS patients, the abnormalities observed in these motor neurons were ameliorated. These findings suggest that Lonrf2 may be useful in establishing new therapeutic strategies for neurodegenerative diseases such as ALS. The results of this research were published in the international scientific journal "Nature Aging" on July 20.
Highlights of this research
The enzyme LONRF2, which selectively ubiquitinates misfolded proteins that cause neurodegenerative diseases, was identified. Mice lacking this enzyme developed age-dependent symptoms of neurodegenerative disease.
Although multiple enzymes that ubiquitinate misfolded proteins had been previously identified, the specific ubiquitination enzymes that function in nerve cells were unknown.
When this enzyme was expressed in motor neurons differentiated from iPS cells derived from patients with amyotrophic lateral sclerosis, the abnormalities observed in the motor neurons were partially ameliorated. These results suggest that this enzyme is expected to be useful for establishing treatments for neurodegenerative diseases.
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