Nucleo-cytoplasmic shuttling of fused in sarcoma (FUS) occurs by a nuclear localization signal (NLS). The majority of clinical amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease) and frontotemporal lobar degeneration (FTLD)-associated FUS mutations occur in its C-terminal NLS sequence.
The PrP-hFUS*R495X transgene has the mouse prion protein (PrP) promoter directing expression of an ALS-associated human R495X truncation mutant (hFUS*R495X) lacking its C-terminal NLS; resulting in significant hFUS mislocalization (abnormal accumulation within the cytoplasm).
The phenotype description below describes FVB-backcrossed PrP-hFUS*R495X mice from founder line PX78. In an attempt to offer transgenic models on well-characterized or multiple genetic backgrounds, transgenes are frequently moved to a genetic background different from that on which they were first characterized. This is the case for the C57BL/6J-congenic PrP-hFUS*R495X transgenic line PX78 (Stock No. 019728). It should be noted that the phenotype could vary from that described below. We will modify the strain description if necessary as published results become available.
The donating investigator reports that hemizygous mice are viable and fertile, with cytoplasmic mislocalization of hFUS*R495X (as shown by immunostaining with a hFUS-specific antibody). Hemizygous mice have ~10-12 copies of the transgene, with ~4-fold greater hFUS expression levels in brain and spinal cord compared to endogenous mouse FUS levels.
In addition, robust cytoplasmic accumulation of hFUS is reported in cortical neurons, deep cerebellar nuclei, lumbar spinal cord anterior horn cells and hippocampal neurons.
Surprisingly, neurons more than one year old appear to tolerate the cytoplasmic hFUS without evidence of abnormal morphological features or obvious neuronal loss. No inclusions are reported (via FUS immunohistochemistry, ubiquitin markers or p62 markers), and cytoplasmic hFUS expression is not shown to alter the normal nuclear prominence of TDP-43 staining. By 8-12 months, hemizygous mice can exhibit neuropathological/electromyographical abnormalities in hindlimb muscles (fibrillation potentials, muscle denervation and reduction in motor unit number estimation).
Hemizygotes sporadically develop a swollen large intestine and evidence of paralytic ileus that cause premature lethality (50% of the original cohort died by ~118 days of age). Homozygous mice were more severely affected, with lower body mass and earlier premature lethality (50% of the original cohort lost by ~59 days of age).
