2025-09-08 バース大学
<関連情報>
- https://www.bath.ac.uk/announcements/new-study-uncovers-how-dna-damage-can-lead-to-motor-neurone-disease/
- https://www.cell.com/iscience/fulltext/S2589-0042(25)01599-8
CFAP410の機能変異体はDNA損傷応答に影響を与え運動ニューロン変性を引き起こす-ALSへの示唆 Functional variants of CFAP410 affect the DNA damage response leading to motor neuron degeneration – Implications for ALS
Ross Ferguson ∙ Vasanta Subramanian
iScience Published:August 9, 2025
DOI:https://doi.org/10.1016/j.isci.2025.113338
Graphical abstract
Highlights
- Endogenously epitope tagged Cfap410 variants in mouse embryonic stem cells were created
- Tagged V20M and R73P variants identified in human populations localize to primary cilia
- Show reduced interactions with the DNA damage response protein in motor neurons
- Impaired DNA damage response in ESC, neural progenitors, and motor neurons
Summary
Mutations in CFAP410, a basal body protein known to be required for the formation of primary cilia, have been identified as risk modifiers in amyotrophic lateral sclerosis (ALS), a devastating late onset neurodegenerative disorder with poor prognosis. CFAP410 is also implicated in the DNA damage response and interacts with Nek1, which has been shown to be mutated in ALS. Herein, we investigated the effect of knocking in an HA epitope tag and functional mutations into the endogenous Cfap410 gene by gene editing in mouse embryonic stem cells (mESCs). We show that primary cilia in these edited mESCs, as well as in the neural progenitors and neurons differentiated from them do not exhibit any significant difference in frequency. However, ESCs, neural progenitors, and neurons with knock-in Cfap410 variants are more susceptible to DNA damage and exhibit impaired interaction with Nek1. Our findings point to DNA damage as a convergent pathway leading to ALS.
