Gut metabolite trimethylamine N-oxide induces aging-associated phenotype of midbrain organoids for the induced pluripotent stem cell-based modeling of late-onset disease

Youngsun Lee; Ji Su Kang; On-Ju Ham; Mi-Young Son; Mi-Ok Lee

doi:10.3389/fnagi.2022.925227

Gut metabolite trimethylamine N-oxide induces aging-associated phenotype of midbrain organoids for the induced pluripotent stem cell-based modeling of late-onset disease

Front Aging Neurosci. 2022 Aug 16:14:925227. doi: 10.3389/fnagi.2022.925227. eCollection 2022.

Authors

Youngsun Lee^{1

2}, Ji Su Kang^{1

2}, On-Ju Ham¹, Mi-Young Son^{1

2}, Mi-Ok Lee^{1

2}

Affiliations

¹ Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.
² Department of Bioscience, Korea University of Science and Technology (UST), Daejeon, South Korea.

Abstract

Brain organoids are valuable research models for human development and disease since they mimic the various cell compositions and structures of the human brain; however, they have challenges in presenting aging phenotypes for degenerative diseases. This study analyzed the association between aging and the gut metabolite trimethylamine N-oxide (TMAO), which is highly found in the midbrain of elderly and Parkinson's disease (PD) patients. TMAO treatment in midbrain organoid induced aging-associated molecular changes, including increased senescence marker expression (P21, P16), p53 accumulation, and epigenetic alterations. In addition, TMAO-treated midbrain organoids have shown parts of neurodegeneration phenotypes, including impaired brain-derived neurotrophic factor (BDNF) signaling, loss of dopaminergic neurons, astrocyte activation, and neuromelanin accumulation. Moreover, we found TMAO treatment-induced pathophysiological phosphorylation of α-synuclein protein at Ser-129 residues and Tau protein at Ser202/Thr205. These results suggest a role of TMAO in the aging and pathogenesis of the midbrain and provide insight into how intestinal dysfunction increases the risk of PD. Furthermore, this system can be utilized as a novel aging model for induced pluripotent stem cell (iPSC)-based modeling of late-onset diseases.

Keywords: TMAO; aging; brain organoid; gut metabolite; midbrain; neurodegenerative disease.