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A low level of expression of C-terminally truncated human FUS causes extensive changes in the spinal cord transcriptome of asymptomatic transgenic mice

ABSTRACT: A number of mutations in a gene encoding RNA-binding protein FUS was linked to the development of a familial form of amyotrophic lateral sclerosis known a FUS-ALS. C-terminal truncations of FUS by a nonsense or frameshift mutations lead to the development of FUS-ALS with a particularly early onset and fast progression. However, even in patients with this aggressive form of the disease the function of motor neurons is not noticeably compromised for at least a couple of decades suggesting that until accumulation in the cytoplasm of pathogenic FUS lacking its C-terminal nuclear localisation signal does not reach 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 level of neuronal expression of a highly aggregation prone and pathogenic form of C-terminally truncated FUS. In contrast to mice with substantially higher level of expression of the same FUS variant that develop severe early onset motor neuron pathology, L-FUS[1-359] mice do not develop any sign of pathology even at old age. Nevertheless, we detected substantial changes in the spinal cord transcriptome of these mice comparing to the wild type littermates. We suggest that at least some of these changes reflect activation of cellular mechanisms compensating to potentially damaging effect of pathogenic FUS production. Further studies of these mechanism might reveal effective target for therapy of FUS-ALS and possibly, other forms of ALS

ORGANISM(S): Mus musculus

PROVIDER: GSE130604 | GEO | 2019/05/03

REPOSITORIES: GEO

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