Low Level of Expression of C-Terminally Truncated Human FUS Causes Extensive Changes in the Spinal Cord Transcriptome of Asymptomatic Transgenic Mice.

Neurochemical Research
Ekaterina A. LysikovaVladimir L Buchman

Abstract

A number of mutations in a gene encoding RNA-binding protein FUS have been linked to the development of a familial form of amyotrophic lateral sclerosis known as FUS-ALS. C-terminal truncations of FUS by either nonsense or frameshift mutations lead to the development of FUS-ALS with a particularly early onset and fast progression. However, even in patients bearing these highly pathogenic mutations the function of motor neurons is not noticeably compromised for at least a couple of decades, suggesting that until cytoplasmic levels of FUS lacking its C-terminal nuclear localisation signal reaches a critical threshold, motor neurons are able to tolerate its permanent production. In order to identify how the nervous system responds to low levels of pathogenic variants of FUS we produced and characterised a mouse line, L-FUS[1-359], with a low neuronal expression level of a highly aggregation-prone and pathogenic form of C-terminally truncated FUS. In contrast to mice that express substantially higher level of the same FUS variant and develop severe early onset motor neuron pathology, L-FUS[1-359] mice do not develop any clinical or histopathological signs of motor neuron deficiency even at old age. Nevertheless, we detected substan...Continue Reading

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Citations

Mar 24, 2021·CNS Neuroscience & Therapeutics·Kirill ChaprovVladimir L Buchman

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Datasets Mentioned

BETA
GSE130604

Methods Mentioned

BETA
transgenic
genotyping
biopsies
PCR
protein folding
genetic modification

Software Mentioned

edgeR
GOplot R
REVIGO
PPLine script
ggplot2
STAR aligner
TapeStation
featureCounts
R
DAVIDWebService R

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