한빛사논문
- 조회983
Chang Woo Chae 1, Jee Hyeon Yoon 1, Jae Ryong Lim 1, Ji Yong Park 1, Ji Hyeon Cho 1, Young Hyun Jung 1, Gee Euhn Choi 2,3, Hyun Jik Lee 4,5, Ho Jae Han 1
1Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 FOUR Future Veterinary Medicine Leading Education & Research Center, Seoul National University, Seoul, South Korea.
2Laboratory of Veterinary Biochemistry, College of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University, Jeju, South Korea.
3Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju, South Korea.
4Laboratory of Veterinary Physiology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, South Korea.
5Institute for Stem Cell and Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Chungbuk, South Korea.
Correspondence : Ho Jae Han
Abstract
Lysosomal dysfunction is a pathogenic link that may explain the causal relationship between diabetes and Alzheimer disease; however, there is no information about the regulation of hyperglycemia in neuronal lysophagy modulating lysosomal function. We examined the effect and related mechanisms of action of high glucose on lysophagy impairment and subsequent Aβ accumulation in human induced pluripotent stem cell (hiPSC)-derived neurons, mouse hippocampal neurons, and streptozotocin (STZ)-induced diabetic mice. High-glucose induced neuronal lysosomal dysfunction through reactive oxygen species-mediated lysosomal membrane permeabilization and lysophagy impairment. Among lysophagy-related factors, the expression of TRIM16 (tripartite motif containing 16) was reduced in high-glucose-treated neuronal cells and the diabetic hippocampus through MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1)-mediated inhibition of TFEB (transcription factor EB) activity. TRIM16 overexpression recovered lysophagy through the recruitment of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3), SQSTM1/p62, and ubiquitin to damaged lysosomes, which inhibited the high-glucose-induced accumulation of Aβ and p-MAPT/tau. In the diabetic mice model, TFEB enhancer recovered lysophagy in the hippocampus, resulting in the amelioration of cognitive impairment. In conclusion, TRIM16-mediated lysophagy is a promising candidate for the inhibition of diabetes-associated Alzheimer disease pathogenesis.
논문정보
- Research article
- 2023년 06월 (BRIC 등록일 2023-07-10)
- 국내 연구진
- 생명과학 > 수의학
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