Larger aggregates of mutant seipin in Celia's Encephalopathy, a new protein misfolding neurodegenerative disease.
Celia's Encephalopathy (MIM #615924) is a recently discovered fatal neurodegenerative syndrome associated with a new BSCL2 mutation (c.985C>T) that results in an aberrant isoform of seipin (Celia seipin). This mutation is lethal in both homozygosity and compounded heterozygosity with a lipodystrophic BSCL2 mutation, resulting in a progressive encephalopathy with fatal outcomes at ages 6-8. Strikingly, heterozygous carriers are asymptomatic, conflicting with the gain of toxic function attributed to this mutation. Here we report new key insights about the molecular pathogenic mechanism of this new syndrome. Intranuclear inclusions containing mutant seipin were found in brain tissue from a homozygous patient suggesting a pathogenic mechanism similar to other neurodegenerative diseases featuring brain accumulation of aggregated, misfolded proteins. Sucrose gradient distribution showed that mutant seipin forms much larger aggregates as compared with wild type (wt) seipin, indicating an impaired oligomerization. On the other hand, the interaction between wt and Celia seipin confirmed by coimmunoprecipitation (CoIP) assays, together with the identification of mixed oligomers in sucrose gradient fractionation experiments can explain the lack of symptoms in heterozygous carriers. We propose that the increased aggregation and subsequent impaired oligomerization of Celia seipin leads to cell death. In heterozygous carriers, wt seipin might prevent the damage caused by mutant seipin through its sequestration into harmless mixed oligomers.
CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, 15782 Santiago de Compostela, Spain.
Alejandro
A
Ruiz-Riquelme
CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, 15782 Santiago de Compostela, Spain.
Sofía
S
Sánchez-Iglesias
Neuropathology Department and Tissue Bank, Fundación CIEN, 28031 Madrid, Spain.
Alberto
A
Rábano
Section of Medical Genetics Dysmorphology, Division of Pediatrics, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, 30120 Murcia, Spain; UCAM-Catholic University of Murcia, CIBERER-ISCIII, Madrid, Spain.
Encarna
E
Guillén-Navarro
Section of Neuropediatrics, Division of Pediatrics, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, 30120 Murcia, Spain; CIBERER-ISCIII, Madrid, Spain.
Rosario
R
Domingo-Jiménez
CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, 15782 Santiago de Compostela, Spain.
Adriana
A
Ramos
CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, 15782 Santiago de Compostela, Spain; Department of Pharmacology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Isaac
I
Rosa
CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, 15782 Santiago de Compostela, Spain.
Ana
A
Senra
Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH - Royal Institute of Technology, SE 171-21 Stockholm, Sweden.
Peter
P
Nilsson
CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, 15782 Santiago de Compostela, Spain; Department of Pharmacology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Ángel
Á
García
CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, 15782 Santiago de Compostela, Spain; Department of Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain. Electronic address: david.araujo@usc.es.
David
D
Araújo-Vilar
CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, 15782 Santiago de Compostela, Spain; Department of Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain. Electronic address: jesus.requena@usc.es.
Jesús R
JR
Requena
D017667:Adipocytes / Q000378:metabolism; D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001927:Brain Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002648:Child; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D066329:Protein Aggregates; D040901:Proteomics; D057165:Proteostasis Deficiencies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
C432679:BSCL2 protein, human; D044388:GTP-Binding Protein gamma Subunits; D066329:Protein Aggregates
BSCL2; Celia's encephalopathy; Intranuclear inclusions; Lipodystrophy; Neurodegeneration; Oligomerization; Phenotype rescue; Progressive encephalopathy; Seipin