Amyotrophic Lateral Sclerosis associated variants of CFAP410 affect the DNA damage response leading to Motor neuron degeneration

Abstract: Mutations in CFAP410, a basal body protein known to be required for the formation of primary cilia, have been recently identified 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 also shown to be mutated in ALS. In this study we have investigated the effect of knocking in a HA epitope tag and two ALS associated mutations into the endogenous Cfap410 gene by gene editing using CRISPR/Cas9 in mouse embryonic stem cells (mESCs). We show that primary cilia in these mESCs, the neural progenitors and neurons differentiated from these mESCs do not exhibit any gross abnormalities. However, ESCs, neural progenitors and neurons with knockin Cfap410 ALS 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.