A new mouse model of ALS may help scientists elucidate the earliest stages of the disease. The knock-in mouse, developed by Elizabeth Fisher and colleagues at University College London in England, exhibits key signs of ALS including motor deficits and progressive motor neuron loss.
The mice, harboring an ALS-linked frameshift mutation in exon 14 in one copy of its own FUS gene, develop symptoms at about one year of age. And at 18 months, about 20% of the motor neurons of these mice degenerated – at least in the spinal cord. No FUS aggregates could be detected.
The findings build on previous studies, which suggest that motor neuron loss occurs in FUS-linked ALS due to a toxic gain of function mechanism (see February 2016 news; Sharma et al., 2016; Shiihashi et al., 2016; Scekic-Zahirovic et al., 2016; Scekic-Zahirovic et al., 2017).
The study is published on November 1 in Brain.
The truncated RNA-binding protein, known as “FUSDelta14”, mislocalized to the cytoplasm of motor neurons of these mice. And, according to subsequent analysis, the protein could be increasingly detected at stress granules.
This mislocalization may contribute to ALS at least in part, due to the inability of FUS to facilitate the synthesis of key proteins needed to keep neurons connected in the brain and spinal cord (see October 2017 news; Qiu et al., 2014; Yokoi et al., 2017).
The model is the first to recapitulate key aspects of adult-onset FUS-linked ALS in mice without overexpression of the disease-linked gene.
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