Studies of the Genotoxicity of Glycidyl Methacrylate (GMA)

The following experiments were conducted to evaluate the genotoxic effects of GMA (glycidyl methacrylale) on mammalian and human cells.(1) Using the absorption spectrum shift method in vitro, we observed that the maximums of calf thymus DNA and GMA were shifted toward longer wavelengths (a change of more than 15nm) and the absorbance decreased after incubation at room temperature for 15min or more.The result indicates that binding of DNA and GMA had occurred.The binding force is strong, not affected by the addition of concentrated sodium chloride solution, and only slightly decreased by the addition of 8 M urea solution.Therefore the bond between DNA and GMA might be covalent.(2) In cell cultures, unscheduled DNA synthesis (UDS) in human and/or rat lymphocyte was induced and DNA semiconserva-tive replication was inhibited by GMA at concentrations of less than 5.2 mM.(3) Sperm abnormality tests and assays of UDS in germ cells of male mice were conducted to study the in vivo genotoxicity of GMA.The results revealed that GMA could damage DNA, increase sperm abnormality frequency, and reduce the number of sperm cells, 1990 Academic Press.Inc.

Contactin-associated protein-like 2(CNTNAP2)mutations impair the essentialα-secretase cleavages,leading to autism-like phenotypes

Mutations in the Contactin-associated protein-like 2(CNTNAP2)gene are associated with autism spectrum disorder(ASD),and ectodomain shedding of the CNTNAP2 protein plays a role in its function.However,key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown,and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive.In this report we showed that CNTNAP2 undergoes sequential cleavages by furin,ADAM10/17-dependent a-secretase and presenilindependent y-secretase.We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96,and the main a-cleavage product C79 by ADAM10 is required for the subsequent y-secretase cleavage to generate CNTNAP2 intracellular domain(CICD).ASD-associated CNTNAP2 mutations impair the a-cleavage to generate C79,and the inhibition leads to ASDIlike repetitive and social behavior abnormalties in the Cntnap2l1254T knock-in mice.Finaly,exogenous expression of 79 improves autism-ike phenotypes in the Cntnap2^(11254T) knock-in and Cntnap2^(-/-)knockout mice.This data demonstrates that the a-secretase is essential for CNTNAP2 processing and its function.Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis,and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.

Clusterin transduces Alzheimer-risk signals to amyloidogenesis

Dear Editor,Deposition of amyloid-β(Aβ)to form neuritic plaque(NP)is the hallmark of Alzheimer’s Disease(AD).Major non-genetic risk factors such as ageing,stroke,diabetes and other conditions facilitate AD pathogenesis via unclear mechanisms.Furthermore,the mechanism underlying NP formation is unclear.Increasing Aβcauses NP in familial AD patients and in transgenic AD mice robustly expressing Aβ,but the NP formation requires long-term Aβaccumulation.