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FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration and associated with aggregation of nuclear RNA-binding proteins (RBPs), including FUS. How FUS aggregation and neurodegeneration are prevented in healthy motor neurons remain critically unanswered questions. Here, we use a combination of ALS patient autopsy tissue and induced pluripotent stem cell-derived neurons to study the effects of FUS mutations on RBP homeostasis. We show that FUS' tendency to aggregate is normally buffered by interacting RBPs, but this buffering is lost when FUS mislocalizes to the cytoplasm due to ALS mutations. The presence of aggregation-prone FUS in the cytoplasm causes imbalances in RBP homeostasis that exacerbate neurodegeneration. However, enhancing autophagy using small molecules reduces cytoplasmic FUS, restores RBP homeostasis and rescues motor function in vivo. We conclude that disruption of RBP homeostasis plays a critical role in FUS-ALS and can be treated by stimulating autophagy.

SUBMITTER: Marrone L

PROVIDER: S-EPMC6570784 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy.

Marrone Lara L Drexler Hannes C A HCA Wang Jie J Tripathi Priyanka P Distler Tania T Heisterkamp Patrick P Anderson Eric Nathaniel EN Kour Sukhleen S Moraiti Anastasia A Maharana Shovamayee S Bhatnagar Rajat R Belgard T Grant TG Tripathy Vadreenath V Kalmbach Norman N Hosseinzadeh Zohreh Z Crippa Valeria V Abo-Rady Masin M Wegner Florian F Poletti Angelo A Troost Dirk D Aronica Eleonora E Busskamp Volker V Weis Joachim J Pandey Udai Bhan UB Hyman Anthony A AA Alberti Simon S Goswami Anand A Sterneckert Jared J

Acta neuropathologica 20190401 1

Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration and associated with aggregation of nuclear RNA-binding proteins (RBPs), including FUS. How FUS aggregation and neurodegeneration are prevented in healthy motor neurons remain critically unanswered questions. Here, we use a combination of ALS patient autopsy tissue and induced pluripotent stem cell-derived neurons to study the effects of FUS mutations on RBP homeostasis. We show that FUS' tendency t ...[more]

PMID: 30937520

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Project description: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.

Dataset Information

FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy.

Publications

FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy.

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