Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities

Abstract

Aging is a natural process that internal gene control and external stimuli mediate. Clinical data pointed out that homozygotic or heterozygotic mutation in the pyrroline-5-carboxylate reductase 1 (PYCR1) gene in humans caused cutis laxa (ARCL) disease, with progeroid appearance, lax and wrinkled skin, joint laxity, osteopenia, and mental retardation phenotypes. In this study, we aimed to generate pycr1 knockout (KO) zebrafish and carried out biochemical characterizations and behavior analyses. Marked apoptosis and senescence were detected in pycr1 KO zebrafish, which started from embryos/larvae stage. Biochemical assays showed that adult pycr1 KO fish have significantly reduced proline and extracellular matrix contents, lowered energy, and diminished superoxide dismutase (SOD) and telomerase activity when compared to the wild type fish, which suggested the pycr1 KO fish may have dysfunction in mitochondria. The pycr1 KO fish were viable; however, displayed progeria-like phenotype from the 4 months old and reach 50% mortality around six months old. In adult stage, we found that pycr1 KO fish showed reduced locomotion activity, aggression, predator avoidance, social interaction interest, as well as dysregulated color preference and circadian rhythm. In summary, we have identified multiple behavioral alterations in a novel fish model for aging with pycr1 gene loss-of-function by behavioral tests. This animal model may not only provide a unique vertebrate model to screen potential anti-aging drugs in the future, but also be an excellent in vivo model towards a better understanding of the corresponding behavioral alterations that accompany aging.

A Novel Function of the Lysophosphatidic Acid Receptor 3 (LPAR3) Gene in Zebrafish on Modulating Anxiety, Circadian Rhythm Locomotor Activity, and Short-Term Memory

“…From the result, two clusters were generated, revealing the degree of similarity between lpar3 KO with pycr1 KO fish and distinct levels of behavior alteration of lpar3 KO fish compared to the wild-type and lepa KO fish ( Figure 8A). This hierarchical clustering is plausible since lpar3 KO fish exhibited similar altered behavior at that of pycr1 KO fish that were studied previously [52]. These behavior-alteration similarities include loss of exploratory behavior, conspecifics social interest, and ability to form a normal shoal, all of which were observed in the lepa KO fish [53].…”

Circadian rhythms in zebrafish (Danio rerio) behaviour and the sources of their variability

“…In addition, the production of melatonin progressively declines during zebrafish ageing (Zhdanova et al, 2008;Kishi et al, 2009), and aged zebrafish display altered expression of the clock genes Bmal1 and Per1 but not Clock1 (Zhdanova et al, 2008). Noticeable changes in circadian behaviour are also reported with premature ageing changes accompanying Pycr1 gene knockout (Liang et al, 2019). In sum, zebrafish ageing is accompanied by disrupted circadian rhythms.…”

Which Zebrafish Strains Are More Suitable to Perform Behavioral Studies? A Comprehensive Comparison by Phenomic Approach

“…In recent decades, molecular biology has obtained a crucial position in many research fields, including the neurobiological mechanisms underlying diseases, drug actions, and behavior. Hence, knockout and transgenic animals, such as Drosophila [1,2], fish [3,4], and rodents [5,6] became popular tools in this field. However, one has to consider the genetic background of the individuals before conducting the experiment, especially in behavioral studies, since nowadays, plentiful evidence of behavioral task differences between the strains exists [7].…”