Mutations: PFN1 G118V
Modification: PFN1: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
Genetic Background: C57Bl/6
Availability: Available through Mahmoud Kiaei
Mutations in profilin, including G118V, are linked to rare familial cases of ALS. The profilin protein is best known for its role in polymerizing actin, but has also been shown to aggregate with RNA and proteins commonly associated with stress granules.
The hPFN1G118V mouse line was created by inserting human PFN1G118V cDNA into a transgene vector downstream from the mouse prion promotor. A control mouse line was also created with the same transgene vector expressing hPFN1WT. Expression ratios of exogenous to endogenous profilin in the spinal cord were approximately 5x and 4x for the PFN1G118V and the PFN1WT. Both mice exhibited transgene expression in the brain and to a lower level in skeletal muscle, but not in the liver (Fil et al, 2016).
Mice expressing hPFN1G118V began to exhibit signs of motor-related phenotypes at 120-130 days, and then progressively deteriorated to end-stage disease at an average of 165-210 days. While gender did not influence the age of disease onset, female mice reached end stage an average of 22 days before males. Mice expressing PFN1WT were phenotypically similar to non-transgenic controls out to 300 days of age.
Initial symptoms of hPFN1G118V mice started with hind limb posture and with age advanced through tremors, limb clasping, muscle weakness, gait abnormalities, and weight loss. At middle stages (140-160 days) mice demonstrated reduced locomotion, stride length, and Rotorod performance. Fully symptomatic hPFN1G118V mice displayed kyphosis (rounded spine) and hind limb paralysis before progressing to end stage, where they were non-ambulatory and were sacrificed when they were unable to right themselves.
Muscle fibers of the gastrocnemius muscle in the hind limb were progressively denervated in parallel with changes in motor phenotypes and culminated in about 40 percent of muscle fibers denervated at end stage. Hind limb muscles demonstrated atrophy as well as reduced amplitude and increased duration of the compound muscle action potential. Additionally, the ventral horn of the spinal cord had progressive loss of neurons from 165 through 202 days of age. Degenerative axons were observed in the ventral root.
Neurons of the ventral horn had lower expression levels of choline acetyltransferase (ChAT) in addition to an increase in TDP-43 puncta in the cytoplasm and nucleus. At end stage there was an increase in astrocytosis and microgliosis in the lumbar spinal cord. The F/G-actin ratio progressively decreased in the spinal cord of hPFN1G118V mice, suggesting that the G118V mutation, which is close to the actin-binding site, could impact the regulation of actin dynamics.
The cerebral cortices of the hPFN1G118V mice had no gross morphology differences compared to control animals. Corticospinal neurons of the motor cortex were decreased at end stage (202 days), but not at mid-stage (150 days) relative to non-transgenic controls.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
Cortical Neuron Loss
At 202 days, there was a decrease in the number of corticospinal neurons of the motor cortex.
Lower Motor Neuron Loss
Progressive loss of ventral horn neurons from 165 through 202 days of age.
Spinal cord motor neurons had TDP-43 puncta.
Astrocytosis and microgliosis were observed in the spinal cord at end stage.
Denervation of gastrocnemius muscle at end stage. Muscle action potential also had reduced amplitude.
At 165 days, hind limb muscle atrophy was observed.
Progressive motor impairments began ~ 120 days. Mice demonstrated tremors, limb clasping, muscle weakness, gait abnormalities, as well as reduced locomotion and decreased performance on the Rotarod.
Body weight peaked ~ 150 days and then progressively decreased.
Mice were sacrificed at an average of 202 days when they were unable to right themselves. Females on average reached 191 days while males attained 213 days.
Last Updated: 03 Mar 2017
- Fil D, DeLoach A, Yadav S, Alkam D, MacNicol M, Singh A, Compadre CM, Goellner JJ, O'Brien CA, Fahmi T, Basnakian AG, Calingasan NY, Klessner JL, Beal FM, Peters OM, Metterville J, Brown RH Jr, Ling KK, Rigo F, Ozdinler PH, Kiaei M. Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease. Hum Mol Genet. 2017 Feb 15;26(4):686-701. PubMed.
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