Nek1-KO Mouse

NEK1, or NIMA-related kinase 1, encodes a serine/threonine kinase. It is involved in multiple cell pathways such as retromer-mediated endosomal trafficking, DNA damage response, and ciliogenesis [2,4]. It also plays a role in processes like glucose metabolism, regulation of RIPK1 activation, and microtubule cytoskeleton and nucleocytoplasmic transport [2,3].

Loss-of-function mutations in NEK1 are associated with human developmental disorders and amyotrophic lateral sclerosis (ALS). In ALS patients, the frequency of NEK1 mutations is 3.1% (including 0.9% loss-of-function (LoF) and 2.3% missense mutations), and these mutations significantly increase the risk of ALS [1]. In a Drosophila model, NEK1 is essential for motor control and survival, and in induced pluripotent stem cell (iPSC)-motor neuron (MN) models, NEK1 deficiency disrupts microtubule homeostasis and nuclear import, which can be restored by stabilizing microtubules [3]. In mice, NEK1 deficiency disrupts blood-brain barrier (BBB) integrity, while genetic inactivation of RIPK1 or metabolic rescue with a ketogenic diet can prevent postnatal lethality and BBB damage [2]. In an ALS patient-derived iPSC-MN model with both C9ORF72 hexanucleotide G4C2 repeat expansion and a NEK1 LoF mutation, NEK1 haploinsufficiency increased pathological C9ORF72 RNA foci in iPSCs and DNA damage levels in iPSC-MNs [4].

In conclusion, NEK1 is a crucial kinase involved in multiple cellular processes. Studies using various genetic models, especially loss-of-function models, have revealed its significant role in diseases like ALS, providing insights into disease mechanisms and potential therapeutic targets for these conditions.