Larger aggregates of mutant seipin in Celia's Encephalopathy, a new protein misfolding neurodegenerative disease
2015 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 83, 44-53 p., 3572Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
Elsevier, 2015. Vol. 83, 44-53 p., 3572
BSCL2, Celia's encephalopathy, Intranuclear inclusions, Lipodystrophy, Neurodegeneration, Oligomerization, Phenotype rescue, Progressive encephalopathy, Seipin, brain protein, unclassified drug, Article, brain disease, brain tissue, BSCL2 gene, Celia encephalopathy, cell death, chromatin immunoprecipitation, controlled study, degenerative disease, female, gene, gene expression, heterozygosity, homozygosity, human, human cell, human tissue, male, molecular pathology, neuropathology, priority journal, proadipocyte, protein aggregation, protein determination, protein expression, protein folding, protein localization, protein protein interaction, proteomics, sucrose gradient
IdentifiersURN: urn:nbn:se:kth:diva-177209DOI: 10.1016/j.nbd.2015.08.006ISI: 000366230000005ScopusID: 2-s2.0-84940916827OAI: oai:DiVA.org:kth-177209DiVA: diva2:874066
QC 201511252015-11-252015-11-172016-01-07Bibliographically approved