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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Nyckelord

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)