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Whole\u2010exome sequencing studies have shown that <jats:italic>NEK1<\/jats:italic> mutations are associated with an increased risk for ALS, where a significant enrichment of <jats:italic>NEK1<\/jats:italic> loss\u2010of\u2010function (LOF) variants were found in individuals with ALS compared to controls. In particular, the p.Arg261His missense variant was associated with significantly increased disease susceptibility. This case series aims to understand the neuropathological phenotypes resulting from <jats:italic>NEK1<\/jats:italic> mutations in ALS. We examined a cohort of three Scottish patients with a mutation in the <jats:italic>NEK1<\/jats:italic> gene and evaluated the distribution and cellular expression of <jats:italic>NEK1<\/jats:italic>, as well as the abundance of phosphorylated TDP\u201043 (pTDP\u201043) aggregates, in the motor cortex compared to age\u2010 and sex\u2010matched control tissue. We show pathological, cytoplasmic TDP\u201043 aggregates in all three <jats:italic>NEK1<\/jats:italic>\u2010ALS cases. NEK1 protein staining revealed no immunoreactivity in two of the <jats:italic>NEK1<\/jats:italic>\u2010ALS cases, indicating a LOF and corresponding to a reduction in <jats:italic>NEK1<\/jats:italic> mRNA as detected by in situ hybridisation. However, the p.Arg261His missense mutation resulted in an increase in <jats:italic>NEK1<\/jats:italic> mRNA molecules and abundant NEK1\u2010positive cytoplasmic aggregates, with the same morphologic appearance, and within the same cells as co\u2010occurring TDP\u201043 aggregates. Here we show the first neuropathological assessment of a series of ALS cases carrying mutations in the <jats:italic>NEK1<\/jats:italic> gene. Specifically, we show that TDP\u201043 pathology is present in these cases and that potential NEK1 LOF can either be mediated through loss of <jats:italic>NEK1<\/jats:italic> translation or through aggregation of NEK1 protein as in the case with p.Arg261His mutation, a potential novel pathological feature of NEK1\u2010ALS.<\/jats:p>","DOI":"10.1111\/bpa.13287","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T22:05:30Z","timestamp":1720649130000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Clinicopathological analysis of <i>NEK1<\/i> variants in amyotrophic lateral sclerosis"],"prefix":"10.1111","volume":"35","author":[{"given":"Olivia M.","family":"Rifai","sequence":"first","affiliation":[{"name":"Centre for Discovery Brain Sciences University of Edinburgh  Edinburgh UK"},{"name":"Department of Neurology Center for Motor Neuron Biology and Disease, Columbia University  New 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