Journal Article

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

Ustyugov, Aleksey, Buchman, Vladimir L., Bachurin, Sergey O., Funikov, Sergei, Flyamer, Ilya M., Ninkina, Natalia, Chaprov, Kirill D., Lysikova, Ekaterina A., Rezvykh, Alexander P., Boyle, Shelagh, Kukharsky, Michail S., Deykin, Alexey V.

2020

Overview

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 substantial changes in the spinal cord transcriptome of these mice compared to their wild type littermates. We suggest that at least some of these changes reflect activation of cellular mechanisms compensating for the potentially damaging effect of pathogenic FUS production. Further studies of these mechanism might reveal effective targets for therapy of FUS-ALS and possibly, other forms of ALS.

• Publisher: Springer US,Springer Nature B.V
• Subject: Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Animals / Asymptomatic Diseases / Biochemistry / Biomedical and Life Sciences / Biomedicine / Cell Biology / Change detection / Frameshift mutation / FUS gene / FUS protein / Gene Expression / Gene Expression Profiling - methods / Humans / Mice / Mice, Transgenic / Motor neurons / Mutation / Nervous system / Neurochemistry / Neurology / Neurons / Neurosciences / Original Paper / Ribonucleic acid / RNA / RNA-binding protein / RNA-Binding Protein FUS - biosynthesis / RNA-Binding Protein FUS - genetics / Spinal cord / Spinal Cord - metabolism / Transcriptome - physiology / Transgenic mice