Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation

Abstract

Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosis in vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration

“…An earlier study has shown that GMF enhances oxidative stress in renal diseases. GMF is normally absent in the kidney but the expression of GMF is inducible in the proximal renal tubules under the stress of proteinuria and in non-brain tissues (Imai et al, 2015 ). Thymus shows the expression of GMF, which is important in T cell development (Utsuyama et al, 2003 ).…”

GMF as an Actin Network Remodeling Factor

“…Overexpression of GMFγ in ovarian cancer cells promotes cell migration and invasion, and alters actin organization, and elevated GMFγ levels correlate with poor patient prognosis. Finally, transgenic mice overexpressing GMFβ have shorter lifespans and show accelerated aging particularly in the kidney, suggesting a role for GMF in aging [100].…”