ABSTRACT
Celia's encephalopathy or progressive encephalopathy with/without lipodystrophy is a neurodegenerative disease with a fatal prognosis in childhood. It is generally caused by the c.985C > T variant in the BSCL2 gene, leading to the skipping of exon 7 and resulting in an aberrant seipin protein (Celia-seipin). To precisely define the temporal evolution and the mechanisms involved in neurodegeneration, lipodystrophy and fatty liver in Celia's encephalopathy, our group has generated the first global knock-in murine model for the aberrant human transcript of BSCL2 (Bscl2Celia/Celia) using a strategy based on the Cre/loxP recombination system. In order to carry out a characterization at the neurological, adipose tissue and hepatic level, behavioral studies, brain PET, metabolic, histological and molecular studies were performed. Around 12% of homozygous and 5.4% of heterozygous knock-in mice showed severe neurological symptoms early in life, and their life expectancy was dramatically reduced. Severe generalized lipodystrophy and mild hepatic steatosis were present in these affected animals, while serum triglycerides and glucose metabolism were normal, with no insulin resistance. Furthermore, the study revealed a reduction in brain glucose uptake, along with patchy loss of Purkinje cells and the presence of intranuclear inclusions in cerebellar cortex cells. Homozygous, non-severely-affected knock-in mice showed a decrease in locomotor activity and greater anxiety compared with their wild type littermates. Bscl2Celia/Celia is the first murine model of Celia's encephalopathy which partially recapitulates the phenotype and severe neurodegenerative picture suffered by these patients. This model will provide a helpful tool to investigate both the progressive encephalopathy with/without lipodystrophy and congenital generalized lipodystrophy.
