Mutation of profilin 1 (PFN1) can cause amyotrophic lateral sclerosis (ALS). To assess how PFN1 mutation causes the disease, we created transgenic rats with human genomic DNA that harbors both the coding and the regulatory sequences of the human PFN1 gene. Selected transgenic lines expressed human PFN1 with or without the pathogenic mutation C71G at a moderate and a comparable level and in the similar pattern of spatial and temporal expression to rat endogenous PFN1. The artificial effects of arbitrary transgene expression commonly observed in cDNA transgenic animals were minimized in PFN1 transgenic rats. Expression of the mutant, but not the wild type, human PFN1 in rats recapitulated the cardinal features of ALS including the progressive loss of motor neurons and the subsequent denervation atrophy of skeletal muscles. Detergent-insoluble PFN1 inclusions were detected as the first pathology in otherwise asymptomatic transgenic rats expressing mutant human PFN1.The findings suggest that protein aggregation is involved in the neurodegeneration of ALS associated with PFN1 mutation. The resulting rat model is useful to mechanistic study on the ALS.

The accumulation of progerin (PG) in patients is responsible for the pathogenesis of Hutchinson-Gilford Progeria Syndrome (HGPS) because it triggers accelerated aging of cells. However, there are few studies on the effects of progerin on tumor cells. Lung cancer is one of the most common malignant cancers with high global morbidity and mortality rates; non-small cell lung cancer accounts for the majority of cases. The purpose of this study was to determine the effects of progerin on A549 cell proliferation, cell cycle, invasion, migration, sensitivity to DNA damaging agents, senescence and apoptosis with a goal of exploring new ideas for lung cancer treatment. Methods: A549 cells overexpressing progerin (A549-PG) and a corresponding blank control (A549-GFP) were constructed by lentiviral infection. A nuclear staining assay was utilized to detect abnormal nuclear morphology. The proliferation, cell cycle, colony formation, invasion and migration abilities of A549-PG were compared with those of A549-GFP via EdU assays, flow cytometry, colony formation experiments, and Matrigel invasion and migration assays, respectively. SA-β-gal staining was used to measure senescence in cells. Results: The expression of progerin was significantly higher in A549-PG than A549-GFP. About 20% of A549-PG possessed abnormal nuclei. Overexpression of progerin in A549 cells inhibited cell proliferation, migration and invasion, and associated proteins (CDK4, pRB, ANLN, MMP7 and MMP9) were downregulated. DNA damage repair was also impaired. Progerin did not cause cells to senesce, and there was no difference in apoptosis. Conclusion: A549-PG generated some cellular changes, including the nuclear skeleton, the cell cycle, DNA damage repair, and migration and invasion abilities. Our data indicate that progerin could cause an imbalance in the steady state in A549 cells and increase their sensitivity to chemotherapeutic drugs.

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