Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia
<p>Pathogenic variants in the <em>UBQLN2</em> gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterized by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by <em>UBQLN2</em> pathogenic variants, particularly <em>C9orf72</em>-linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 44 genotypically diverse amyotrophic lateral sclerosis cases with or without frontotemporal dementia, including eight cases with <em>UBQLN2</em> variants [resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases) and p.P497L (three cases)].</p> <p>Using multiplexed (five-label) fluorescent immunohistochemistry, we mapped the co-localization of ubiquilin 2 with phosphorylated TDP-43, dipeptide repeat aggregates and p62 in the hippocampus of controls (<em>n</em> = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (<em>n</em> = 20), unknown familial (<em>n</em> = 3), <em>SOD1</em>-linked (<em>n</em> = 1), <em>FUS</em>-linked (<em>n</em> = 1), <em>C9orf72</em>-linked (<em>n</em> = 5) and <em>UBQLN2</em>-linked (<em>n</em> = 8) cases.</p> <p>We differentiate between (i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins; and (ii) ubiquilin 2 self-aggregation promoted by <em>UBQLN2</em> pathogenic variants that cause amyotrophic lateral sclerosis and/or frontotemporal dementia. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wild-type ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wild-type to aggregate independently of driving factors.</p> <p>This neuropathological signature can be used to assess the pathogenicity of <em>UBQLN2</em> gene variants and to understand the mechanisms of <em>UBQLN2</em>-linked disease.</p>
Digital object identifier (DOI): 10.1093/brain/awae140