ALS-FUS pathology revisited: singleton FUS mutations and an unusual case with both a FUS and TARDBP mutation.

Andrew King,Matthew Nolan,Olimpia Curran,Bradley Smith,Christopher E Shaw,Claire Troakes,Safa Al-Sarraj,Caroline Vance

doi:10.1186/s40478-015-0235-x

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https://doi.org/10.1186/s40478-015-0235-x

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Abstract

IntroductionMutations in the FUS gene have been shown to be a rare cause of amyotrophic lateral sclerosis (ALS-FUS) and whilst well documented clinically and genetically there have been relatively few neuropathological studies.Recent work suggested a possible correlation between pathological features such as frequency of basophilic inclusions in neurons and rate of clinical decline, other studies have revealed a discrepancy between the upper motor neuron features detected clinically and the associated pathology. The purpose of this study was to describe the pathological features associated with more recently discovered FUS mutations and reinvestigate those with well recognised mutations in an attempt to correlate the pathology with mutation and/or clinical phenotype. The brains and spinal cords of seven cases of ALS-FUS were examined neuropathologically, including cases with the newly described p.K510E mutation and a case with both a known p.P525L mutation in the FUS gene and a truncating p.Y374X mutation in the TARDBP gene.ResultsThe neuropathology in all cases revealed basophilic and FUS inclusions in the cord. The density and type of inclusions varied markedly between cases, but did not allow a clear correlation with clinical progression. Only one case showed significant motor cortical pathology despite the upper motor neuron clinical features being evident in 4 patients. The case with both a FUS and TARDBP mutation revealed FUS positive inclusions but no TDP-43 pathology. Instead there were unusual p62 positive, FUS negative neuronal and glial inclusions as well as dot-like neurites.ConclusionsThe study confirms cases of ALS-FUS to be mainly a lower motor neuron disease and to have pathology that does not appear to neatly correlate with clinical features or genetics. Furthermore, the case with both a FUS and TARDBP mutation reveals an intriguing pathological profile which at least in part involves a very unusual staining pattern for the ubiquitin-binding protein p62.

Highlights

Mutations in the Fused in sarcoma (FUS) gene have been shown to be a rare cause of amyotrophic lateral sclerosis (ALS-FUS) and whilst well documented clinically and genetically there have been relatively few neuropathological studies.Recent work suggested a possible correlation between pathological features such as frequency of basophilic inclusions in neurons and rate of clinical decline, other studies have revealed a discrepancy between the upper motor neuron features detected clinically and the associated pathology
Genetics Six non-synonymous and one truncation FUS mutation were identified in seven familial ALS patients by direct sequencing
ALS associated with TDP-43 positive inclusions (ALS-TDP) and frontotemporal lobar degeneration with TDP-43 positive inclusions (FTLD-TDP) are believed to represent a clinicopathological spectrum, where some patients have clinical and pathological features of a frontotemporal dementia and ALS (FTLD-MND/ALS)

Summary

Introduction

Mutations in the FUS gene have been shown to be a rare cause of amyotrophic lateral sclerosis (ALS-FUS) and whilst well documented clinically and genetically there have been relatively few neuropathological studies.Recent work suggested a possible correlation between pathological features such as frequency of basophilic inclusions in neurons and rate of clinical decline, other studies have revealed a discrepancy between the upper motor neuron features detected clinically and the associated pathology. The discovery of the TAR DNA binding protein 43 (TDP-43) as a component of the neuronal inclusions in most cases of amyotrophic lateral sclerosis (ALS), and many cases of frontotemporal lobar degeneration (FTLD) marked a significant advance in the research into these devastating neurodegenerative diseases [1, 2]. Two years later another RNA binding protein termed fused in sarcoma (FUS) Another publication with reference to genetic and clinical, but not pathological analysis, has indicated that truncating mutations in the FUS gene may give rise to a more aggressive phenotype than missense mutations [16]

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