TY - JOUR
T1 - Larger aggregates of mutant seipin in Celia's Encephalopathy, a new protein misfolding neurodegenerative disease
AU - Ruiz-Riquelme, Alejandro
AU - Sánchez-Iglesias, Sofía
AU - Rábano, Alberto
AU - Guillén-Navarro, Encarna
AU - Domingo-Jiménez, Rosario
AU - Ramos, Adriana
AU - Rosa, Isaac
AU - Senra, Ana
AU - Nilsson, Peter
AU - García, Ángel
AU - Araújo-Vilar, David
AU - Requena, Jesús R.
N1 - Funding Information:
The name Celia's Encephalopathy is a tribute to Celia's memory and was chosen in agreement with her parents, to whom we are deeply indebted for their collaboration and commitment to research. We thank Ana Senra, CIMUS Biomedical Research Institute, for assistance with histopathology, Dr. Justin Rochford for his suggestions and advice and Dr. Daisuke Ito for kindly providing the Myc-wt seipin plasmid. This work was supported by Instituto de Salud Carlos III (grant number PI 10/02873 and PI13/00314 ), the European Regional Development Fund, FEDER, Xunta de Galicia (grant number 10PXIB208013PR ) and Fundación MEHUER (Miguel Gil grant) . AG acknowledges support from the Spanish Ministry of Economy and Competitiveness (grant number SAF2013-45014-R ). ARR is the recipient of an IDIS pre-doctoral fellowship. SSI is a Research Fellow granted by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP).
Publisher Copyright:
© 2015 Elsevier Inc..
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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.
AB - 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.
KW - BSCL2
KW - Celia's encephalopathy
KW - Intranuclear inclusions
KW - Lipodystrophy
KW - Neurodegeneration
KW - Oligomerization
KW - Phenotype rescue
KW - Progressive encephalopathy
KW - Seipin
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U2 - 10.1016/j.nbd.2015.08.006
DO - 10.1016/j.nbd.2015.08.006
M3 - Article
C2 - 26282322
AN - SCOPUS:84940916827
VL - 83
SP - 44
EP - 53
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
ER -