Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: N/A
Genetic Background: C57BL/6J
Availability: Viral construct available through Leonard Petrucelli.
The six-nucleotide (GGGGCC) repeat expansion in C9ORF72 encodes five dipeptide repeat proteins that accumulate in ALS/FTD: glycine-arginine (GR), proline-arginine (PR), glycine-alanine (GA), proline-alanine (PA), and glycine-proline (GP). The GFP–(GR)100 mouse is the first mouse model that specifically expresses poly(GR). To create this model, an adeno-associated viral (AAV) vector encoding 100 GR repeats tagged with green fluorescent protein was injected into the ventricles of neonatal mice. GFP–(GR)100 mice exhibit progressive neuron loss and age-dependent motor and cognitive impairments.
Poly(GR) was found throughout the brain but was barely detectable in spinal cord. This dipeptide repeat was diffusely distributed in the cytoplasm, where it co-localized with ribosomal sub-units and the translation initiation factor eIF3η. Poly(GR) did not form cytoplasmic inclusions, and TDP-43-positive inclusions were very infrequent. No defects in nuclear envelopes were apparent.
Brain weight decreased from 1.5 to 6 months of age, the oldest age studied, reflecting the progressive loss of cortical and hippocampal (CA1-3) neurons: At 6 months, the brains of GFP-(GR)100 mice weighed only about half of those of controls expressing GFP, and had only one-third the number of cortical neurons and one-quarter the number of hippocampal neurons. There was also an age-dependent decline in the number of cerebellar Purkinje cells in the brains of GFP-(GR)100 mice. Neuron loss did not occur in the spinal cord.
Astrogliosis and microgliosis were already apparent in cortex and hippocampus at 6 weeks of age.
By 3 months of age, GFP-(GR)100 mice had shorter latencies to fall in the rotarod test, compared with GFP-expressing controls. Motor deficits worsened with age, so that by 6 months, GFP-(GR)100 mice travelled shorter distances in the open field test, and had more falls during the rod-walk and wire-hang tests, compared with 3-month mice or with GFP controls. Impairments in cued, but not contextual, fear conditioning were apparent at 6 months.
Transcriptomic analyses revealed expression changes mainly in genes related to immune responses, constituents of ribosomes, and protein translation.
An adeno-associated viral (AAV) vector encoding 100 GR repeats tagged with green fluorescent protein was injected into the ventricles of C57BL/6J pups on postnatal day zero. Expression is driven by a CMV-enhanced chicken β-actin promoter.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Lower Motor Neuron Loss
- Body Weight
- NMJ Abnormalities
- Muscle Atrophy
- Premature Death
Cortical Neuron Loss
Fewer cortical neurons than controls, observed as early as 6 weeks of age.
Lower Motor Neuron Loss
Not observed up to 6 months of age.
Very rare TDP-43 inclusions, observed at 6 months.
Astrogliosis and microgliosis in cortex and hippocampus, observed at 6 weeks.
Progressive motor deficits, seen in open-field, rotarod, rod-walk, and wire-hang tests.
Normal at 6 months of age.
Last Updated: 21 Sep 2018