RESUMO
Purpose: Previous studies have reported Caspase-1 (Casp1) is upregulated in mouse models of Juvenile X-linked Retinoschisis (XLRS), however no functional role for Casp1 in disease progression has been identified. We performed electroretinogram (ERG) and standardized optical coherence tomography (OCT) in mice deficient in the Retinoschisin-1 (Rs1) and Casp1 and Caspase-11 (Casp11) genes (Rs1-KO;Casp1/11-/- ) to test the hypothesis that Casp1 may play a role in disease evolution and or severity of disease. Currently, no studies have ventured to investigate the longer-term effects of Casp1 on phenotypic severity and disease progression over time in XLRS, and specifically the effect on electroretinogram. Methods: Rs1-KO;Casp1/11-/- mice were generated by breeding Rs1-KO mice with Casp1/11-/- mice. OCT imaging was analyzed at 2-, 4-, and 15-16 months of age. Outer nuclear layer (ONL) thickness and adapted standardized cyst severity score were measured and averaged from 4 locations 500 µm from the optic nerve. Adapted standardized cyst severity score was 1: absent cysts, 2: <30 µm, 3: 30-49 µm, 4: 50-69 µm, 5: 70-99 µm, 6: >99 µm. Electroretinograms (ERG) were recorded in dark-adapted and light-adapted conditions at 2 and 4 months. Results obtained from Rs1-KO and Rs1-KO;Casp1/11-/- eyes were compared with age matched WT control eyes at 2 months. Results: Intraretinal schisis was not observed on OCT in WT eyes, while schisis was apparent in most Rs1-KO and Rs1-KO;Casp1/11-/- eyes at 2 and 4 months of age. There was no difference in the cyst severity score from 2 to 4 months of age, or ONL thickness from 2 to 16 months of age between Rs1-KO and Rs1-KO;Casp1/11-/- eyes. ERG amplitudes were similarly reduced in Rs1-KO and Rs1-KO;Casp1/11-/- compared to WT controls at 2 months of age, and there was no difference between Rs1-KO and Rs1-KO;Casp1/11-/- eyes at 2 or 4 months of age, suggesting no impact on the electrical function of photoreceptors over time in the absence of Casp1. Conclusion: Although Casp1 has been reported to be significantly upregulated in Rs1-KO mice, our preliminary data suggest that removing Casp1/11 does not modulate photoreceptor electrical function or alter the trajectory of the retinal architecture over time.
RESUMO
Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine protein kinase belonging to the ROCO protein family. Within the kinase domain of LRRK2, a point mutation known as LRRK2 G2019S has emerged as the most prevalent variant associated with Parkinson's disease. Recent clinical studies have indicated that G2019S carriers have an elevated risk of cancers, including colon cancer. Despite this observation, the underlying mechanisms linking LRRK2 G2019S to colon cancer remain elusive. In this study, employing a colitis-associated cancer (CAC) model and LRRK2 G2019S knock-in (KI) mouse model, we demonstrate that LRRK2 G2019S promotes the pathogenesis of colon cancer, characterized by increased tumor number and size in KI mice. Furthermore, LRRK2 G2019S enhances intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, KI mice exhibit heightened susceptibility to DSS-induced colitis, with inhibition of LRRK2 kinase activity ameliorating colitis severity and CAC progression. Our investigation also reveals that LRRK2 G2019S promotes inflammasome activation and exacerbates gut epithelium necrosis in the colitis model. Notably, GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice. Taken together, our findings offer experimental evidence indicating that the gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, suggesting LRRK2 as a potential therapeutic target in colon cancer patients exhibiting hyper LRRK2 kinase activity.