Unravelling the Pathogenesis of Celia’s Encephalopathy (PELD): the Role of Seipin in Neurodegeneration, Lipodystrophy, and other Tissue Damage in a Humanized Murine Model

• Autores: Silvia Cobelo Gómez
• Directores de la Tesis: David Araujo Vilar (dir. tes.), Sofía Sánchez Iglesias (dir. tes.)
• Lectura: En la Universidade de Santiago de Compostela ( España ) en 2025
• Idioma: inglés
• Tribunal Calificador de la Tesis: Justin James Rochford (presid.), José María Óscar Prieto González (secret.), Manuel Antonio Botana López (voc.)
• Programa de doctorado: Programa de Doctorado en Endocrinología por la Universidad de Santiago de Compostela y la Universidad de Vigo
• Materias:
  • Ciencias médicas
    • Medicina interna
      • Endocrinología
• Enlaces
  • Tesis en acceso abierto en: MINERVA
• Resumen

  • The BSCL2 gene encodes seipin, a protein essential for lipid droplet formation and nerve impulse transmission. Variants in BSCL2 lead to congenital generalized lipodystrophy type 2, CGL2, a rare autosomal recessive disorder characterized by a lack of adipose tissue, early-onset hypertrglyceridemia, hyperinsulinemia, hypoleptinemia, and severe insulin resistance, which can cause acanthosis nigricans and non-ketotic diabetes mellitus. Celias encephalopathy or progressive encephalopathy with or without lipodystrophy is a neurodegenerative disorder linked to BSCL2 variants, particularly c.985CT in exon 7, leading to the production of an aberrant Celia seipin variant. Homozygous patients may not display classic generalized lipodystrophy but can exhibit hypertriglyceridemia and hepatomegaly, while compound heterozygotes often show CGL2 symptoms. Neurologically, patients suffer from psychomotor retardation, neurological regression, myoclonic epilepsy, spastic tetraparesis, and encephalopathy, often resulting in death before age nine. The pathogenic mechanism of this disease appears to involve a toxic gain-of-function. Heterozygous carriers are typically asymptomatic due to the wild type seipins interaction with Celia seipin, reducing its toxicity. Understanding the disorder's pathogenic mechanisms is difficult due to its rarity and severity, with the brain being the most affected organ. To explore the molecular mechanisms of neurodegeneration, lipodystrophy, and non-alcoholic steatohepatitis in Celias encephalopathy, this study developed two murine models: a global murine model for the aberrant human BSCL2 transcript using Cre/loxP recombination, and a seipin-deficient murine model with disrupted seipin protein production. Only the KI mice carrying the human BSCL2 transgene mutation exhibited symptoms similar to those in human patients, such as ponderal stagnation, abnormal limb crossing, kyphosis, tremor, myoclonus, tail spasticity, and paraparesis or paraplegia. However, only 11.9% of homozygous KI mice showed clear neurodegeneration, while 5.4% of heterozygous KI mice developed neurological symptoms, suggesting possible differences between human and mouse protective mechanisms. Further analysis revealed increased glial cell proliferation in the thoracic spinal cord and Purkinje cell loss in the cerebellum of S.A. mice. Interestingly, higher transgene expression was observed only in the cortex of severely affected, S.A., homozygous mice, suggesting differences in BSCL2 gene expression between humans and mice. The study also examined seipin's role in mitochondrial and peroxisome function, noting reduced expression of Sod1 and Sod2 in the cortex of S.A. mice. Behavioural studies indicated that S.A. mice exhibited diminished locomotion and increased anxiety, while their cognitive functions remained normal. No significant behavioural differences were noted between homozygous animals from the KI and KO murine models, suggesting that the absence of the murine Bscl2 gene, rather than the presence of the human transgene, might explain some behavioural changes. Ubiquitination in the cerebellum was also observed, with ubiquitin-reactive nuclear inclusions positive for seipin in S.A. mice, supporting the theory that Celia-seipin aggregation plays a key role in disease through a toxic gain-of-function mechanism. In addition to neurological symptoms, S.A. homozygous animals showed severe generalized lipodystrophy and mild hepatic steatosis. Despite these metabolic issues, their serum and liver triglyceride levels and glucose metabolism remained normal, although they exhibited severe hypoleptinemia. Non-S.A. homozygous mice showed adipose tissue depletion, hyperinsulinemia, and insulin resistance, mimicking the metabolic characteristics of CGL2 and Celias encephalopathy in humans, though without diabetes mellitus or hypertriglyceridemia. In the liver, fat deposition caused hepatomegaly, steatohepatitis, and fibrosis, but no cirrhosis was observed. Both KI and KO homozygous mice displayed triglyceride accumulation in the liver, highlighting potential differences between mouse and human liver physiology. These mice also exhibited enlarged organs, along with renal damage characterized by mesangial expansion and arteriolar hyalinization. Ultimately, this study introduces a global murine model that partially mimics the severe neurodegenerative features of Celias encephalopathy, along with a model replicating the typical phenotype of CGL2 through seipin depletion. Although these models do not perfectly mirror the human disease, they represent significant progress in understanding seipinopathies. These models provide crucial tools for studying the pathogenesis and exploring potential therapies for these rare genetic disorders. Further research and refinement of these models will be key in bridging the gap between murine and human manifestations of these conditions.