1. Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia.
- Author
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Thumbadoo, Kyrah M, Dieriks, Birger V, Murray, Helen C, Swanson, Molly E V, Yoo, Ji Hun, Mehrabi, Nasim F, Turner, Clinton, Dragunow, Michael, Faull, Richard L M, Curtis, Maurice A, Siddique, Teepu, Shaw, Christopher E, Newell, Kathy L, Henden, Lyndal, Williams, Kelly L, Nicholson, Garth A, and Scotter, Emma L
- Subjects
AMYOTROPHIC lateral sclerosis ,FRONTOTEMPORAL dementia ,SPINAL cord ,MOTOR neurons ,MOTOR cortex ,FRONTOTEMPORAL lobar degeneration - Abstract
Pathogenic variants in the UBQLN2 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 UBQLN2 pathogenic variants, particularly C9orf72 -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 UBQLN2 variants [resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases) and p.P497L (three cases)]. 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 (n = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (n = 20), unknown familial (n = 3), SOD1 -linked (n = 1), FUS -linked (n = 1), C9orf72 -linked (n = 5) and UBQLN2 -linked (n = 8) cases. We differentiate between (i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins; and (ii) ubiquilin 2 self-aggregation promoted by UBQLN2 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. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2 -linked disease. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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