The role of Cdkal1-mediated tRNA modification in peripheral neuropathy

2017 Fiscal Year Final Research Report

• Project/Area Number: 15H04850
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: Kazuhito Tomizawa 熊本大学, 大学院生命科学研究部(医), 教授 (40274287)
• Co-Investigator(Renkei-kenkyūsha): ARAKI Eiichi 熊本大学, 大学院生命科学研究部, 教授 (10253733) ; USUKU Koichiro 熊本大学, 医学部附属病院, 教授 (30281223) ; KAKUMA Tatsuyuki 久留米大学, バイオ統計センター, 教授 (50341540) ; WEI Fan-Yan 熊本大学, 大学院生命科学研究部, 准教授 (90555773)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 糖尿病 / 神経障害 / tRNA / 翻訳 / 末梢神経

Outline of Final Research Achievements

Genetic variations in CDKAL1 have been associated with the development of type 2 diabetes. CDKAL1 is a methylthiotransferase that catalyzes 2-methylthi modification of tRNALys(UUU). The ms2 modification is important for accurate decoding of Lys codon in Proinsulin. In addition to Proinsulin, Lys is also critical for the processing of various neurotropic factors. We hypothesized that the dysregulation of CDKAL1 might cause aberrant translation of neurotropic factors, and lead to the development of neuropathy. To test this hypothesis, we investigated the sensory functions of peripheral nerves in Cdkal1-knockout mice. Cdkal1-deficiency induced peripheral neuropathy independent of glucose intolerance. Cdkal1-deficient mice exhibited loss of CGRP- and IB4-positive neurons in DRG. Cdkal1-deficient mice exhibited loss of nerve fibers in footpad. BDNF were reduced in DRG of Cdkal1KO mice.These results suggest that dysfunction of Cdkal1 may critical for development of diabetic neuropathy.

Free Research Field

生理学