Functional characterization of a FUS mutant zebrafish line as a novel genetic model for ALS

NEUROBIOLOGY OF DISEASE

卷:142

Article

Bourefis, Annis-Rayan^1,2  Campanari, Maria-Letizia^1,2  Buee-Scherrer, Valerie³  Kabashi, Edor^1,2 

[1] Paris Descartes Univ, Imagine Inst, Inst Natl Sante & Rech Med INSERM, Unite 1163, F-75015 Paris, France

[2] Univ Paris 06, Univ Pierre & Marie Curie UPMC, Inst Cerveau & Moelle Epiniere ICM, INSERM Unite 1127,Sorbonne Univ,CNRS,Unite Mixte, F-75013 Paris, France

[3] Univ Lille, Alzheimer & Tauopathies, CHU Lille, INSERM, Lille, France

关键词: Amyotrophic lateral sclerosis (ALS);    Motor neuron;    Neuromuscular junction;    Zebrafish;    FUS;    Tau Frontotemporal dementia;    Genetics;    Neurodegeneration;   

DOI  :  10.1016/j.nbd.2020.104935

来源: Elsevier

【 摘 要 】

Mutations in Fused in sarcoma (FUS), an RNA-binding protein, are known to cause Amyotrophic Lateral Sclerosis (ALS). However, molecular mechanisms due to loss of FUS function remain unclear and controversial. Here, we report the characterization and phenotypic analysis of a deletion mutant of the unique FUS orthologue in zebrafish where Fus protein levels are depleted. The homozygous mutants displayed a reduced lifespan as well as impaired motor abilities associated with specific cellular deficits, including decreased motor neurons length and neuromuscular junctions (NMJ) fragmentation. Furthermore, we demonstrate that these cellular impairments are linked to the misregulation of mRNA expression of acetylcholine receptor (AChR) subunits and histone deacetylase 4, markers of denervation and reinnervation processes observed in ALS patients. In addition, fus loss of function alters tau transcripts favoring the expression of small tau isoforms. Overall, this new animal model extends our knowledge on FUS and supports the relevance of FUS loss of function in ALS physiopathology.