RT Journal Article
T1 Larger aggregates of mutant seipin in Celia's Encephalopathy, a new protein misfolding neurodegenerative disease
A1 Sánchez Iglesias, Sofía
A1 Ruiz Riquelme, Alejandro Iván
A1 Rábano, Alberto
A1 Guillén-Navarro, Encarna
A1 Domingo-Jiménez, Rosario
A1 Ramos, Adriana
A1 Rosa, Isaac
A1 Senra, Ana
A1 Nilsson, Peter
A1 García, Ángel
A1 Araujo-Vilar, David
A1 Rodríguez Requena, Jesús
K1 Seipin
K1 BSCL2
K1 Neurodegeneration
K1 Lipodystrophy
K1 Intranuclear inclusions
K1 Progressive encephalopathy
K1 Celia's encephalopathy
K1 Oligomerization
K1 Phenotype rescue
AB Celia's Encephalopathy (MIM #615924) is a recently discovered fatal neurodegenerative syndrome associated with a new BSCL2  mutation (c.985CNT) 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. 
PB Neurobiology of Disease
YR 2015
FD 2015
LK http://hdl.handle.net/10347/32038
UL http://hdl.handle.net/10347/32038
LA eng
NO Alejandro Ruiz-Riquelme, Sofía Sánchez-Iglesias, Alberto Rábano, Encarna Guillén-Navarro, Rosario Domingo-Jiménez, Adriana Ramos, Isaac Rosa, Ana Senra, Peter Nilsson, Ángel García, David Araújo-Vilar, Jesús R. Requena, Larger aggregates of mutant seipin in Celia's Encephalopathy, a new protein misfolding neurodegenerative disease, Neurobiology of Disease, Volume 83, 2015, Pages 44-53, ISSN 0969-9961, https://doi.org/10.1016/j.nbd.2015.08.006.
DS Minerva
RD 28 abr 2026