2024-01-08 バース大学
◆「Angiogenin(ANG)」遺伝子の研究で、健康な状態のANGが神経細胞の発達に重要な役割を果たすことが判明。しかし、変異すると発達が遅れ、神経発達異常が見られ、神経細胞の変性が早期に引き起こされることが示唆された。研究者はこれが病気の感受性や発症に影響する可能性があり、早期介入ができる可能性があると述べ、さらなる研究が必要だと強調。家族のミニ脳実験でもANG変異の影響が確認され、これにより将来的に遺伝子療法が可能になるかもしれない。
<関連情報>
- https://www.bath.ac.uk/announcements/disease-in-a-dish-model-sheds-light-on-the-triggers-for-some-forms-of-dementia/
- https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6244
アンジオジェニンの変異を持つ皮質オルガノイドでは、神経幹細胞のホメオスタシスが影響を受けている Neural stem cell homeostasis is affected in cortical organoids carrying a mutation in Angiogenin
Ross Ferguson, Michael A van Es, Leonard H van den Berg, Vasanta Subramanian
The Journal of Pathology Published: 05 January 2024
DOI:https://doi.org/10.1002/path.6244
Abstract
Mutations in Angiogenin (ANG) and TARDBP encoding the 43 kDa transactive response DNA binding protein (TDP-43) are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). ANG is neuroprotective and plays a role in stem cell dynamics in the haematopoietic system. We obtained skin fibroblasts from members of an ALS-FTD family, one with mutation in ANG, one with mutation in both TARDBP and ANG, and one with neither mutation. We reprogrammed these fibroblasts to induced pluripotent stem cells (iPSCs) and generated cortical organoids as well as induced stage-wise differentiation of the iPSCs to neurons. Using these two approaches we investigated the effects of FTD-associated mutations in ANG and TARDBP on neural precursor cells, neural differentiation, and response to stress. We observed striking neurodevelopmental defects such as abnormal and persistent rosettes in the organoids accompanied by increased self-renewal of neural precursor cells. There was also a propensity for differentiation to later-born neurons. In addition, cortical neurons showed increased susceptibility to stress, which is exacerbated in neurons carrying mutations in both ANG and TARDBP. The cortical organoids and neurons generated from patient-derived iPSCs carrying ANG and TARDBP gene variants recapitulate dysfunctions characteristic of frontotemporal lobar degeneration observed in FTD patients. These dysfunctions were ameliorated upon treatment with wild type ANG. In addition to its well-established role during the stress response of mature neurons, ANG also appears to play a role in neural progenitor dynamics. This has implications for neurogenesis and may indicate that subtle developmental defects play a role in disease susceptibility or onset. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
