Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases
ABSTRACT Heterozygous mutations in the Seipin/BSCL2 gene have recently been identified in two autosomal dominant motor neuron diseases, distal hereditary motor neuropathy type V and Silver's syndrome. Seipin protein is reportedly a transmembrane protein localized in the endoplasmic reticulum (ER). N88S and S90L mutations of this protein disrupt its glycosylation, resulting in its aggregation, but the mechanism of neurodegeneration remains unclear. To clarify the molecular pathogenesis of seipin-related motor neuron diseases, we expressed wild-type and mutant seipin proteins in neuronal and nonneuronal cells.
Coexpression of human seipin and ubiquitin showed that seipin is polyubiquitinated and its ubiquitination is enhanced by mutation. Treatment of cells with a proteasome inhibitor increased the amounts of mutant seipin in the cells, suggesting that they are degraded through the ER-associated degradation pathway. Immunoprecipitation studies showed that mutant seipin stably binds to the ER chaperone calnexin, indicating accumulation of unfolded mutant seipin in the ER. Furthermore, expression of mutant seipin increased the level of ER stress-mediated molecules and induced apoptosis in cultured cells.
These findings demonstrate that seipin/BSCL2-related motor neuron diseases are novel conformational diseases, and we suspect that they are tightly associated with ER stress-mediated cell death.
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ABSTRACT: Congenital generalized lipodystrophy (CGL) is a genetic disorder characterized by near complete loss of adipose tissue along with increased ectopic fat storage in other organs including liver and muscle. Of the four CGL types, Berardinelli-Seip Congenital lipodystrophy type 2 (BSCL2), resulting from mutations in the BSCL2/seipin gene, exhibits the most severe lipodystrophic phenotype with loss of both metabolic and mechanical adipose depots. The majority of Seipin mutations cause C-terminal truncations, along with a handful of point mutations. Seipin localizes to the ER and is composed of a conserved region including a luminal loop and two transmembrane domains, plus cytosolic N- and C-termini. Animal models deficient in seipin recapitulate the human lipodystrophic phenotype. Cells isolated from seipin knockout mouse models also exhibit impaired adipogenesis. Mechanistically, seipin appears to function as a scaffolding protein to bring together interacting partners essential for lipid metabolism and lipid droplet formation during adipocyte development. Moreover, cell line and genetic studies indicate that seipin functions in a cell-autonomous manner. Here we will provide a brief overview of the genetic association of the CGLs, and focus on the current understanding of differential contributions of distinct seipin domains to lipid storage and adipogenesis. We will also discuss the roles of seipin-interacting partners, including lipin 1 and 14-3-3β, in mediating seipin-dependent regulation of cellular pathways such as actin cytoskeletal remodeling.Bioscience Reports 09/2014; DOI:10.1042/BSR20140114 · 2.85 Impact Factor
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ABSTRACT: The lipid droplet (LD) is a phylogenetically conserved organelle. In eukaryotes, it is born from the endoplasmic reticulum, but unlike its parent organelle, LDs are the only known cytosolic organelles that are micellar in structure. LDs are implicated in numerous physiological and pathophysiological functions. Many aspects of the LD has captured the attention of diverse scientists alike and has recently led to an explosion in information on the LD biogenesis, expansion and fusion, identification of LD proteomes and diseases associated with LD biology. This review will provide a brief history of this fascinating organelle and provide some contemporary views of unanswered questions in LD biogenesis.Critical Reviews in Biochemistry and Molecular Biology 07/2014; 49(4). DOI:10.3109/10409238.2014.931337 · 5.81 Impact Factor
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ABSTRACT: Seipinopathies are a group of inherited diseases affecting upper and lower motor neurons due to mutations in the Berardinelli–Seip congenital lipodystrophy 2 gene (BSCL2). We report a French family carrying the N88S mutation in the BSCL2 gene. A 12-yr-old girl complained of bilateral asymmetrical pes cavus with right hand motor deficit and amyotrophy, asymmetrical leg amyotrophy and pyramidal signs. Electrophysiological examination showed axonal asymmetrical motor neuropathy with distal predominance. Her father complained of right hand rest tremor with bilateral hand weakness. Physical examination revealed left leg, hand and forearm amyotrophy, akinesia and right arm rigidity, brisk reflexes in the lower limbs and bilateral Babinski sign. Nerve conduction studies showed distal asymmetrical axonal neuropathy with slight sensitive impairment with moderate decrease of nerve conduction velocity in some nerves. DNA sequencing revealed the presence of the known N88S mutation in the BSCL2 gene (dideoxy-nucleotide method on a 3730 DNA Analyzer, Life Technologies). BSCL2 gene mutations are associated with a wide spectrum of clinical and electrophysiological phenotypes and should be suspected in cases of distal hereditary motor neuropathy with pyramidal signs or early hand involvement. There may also be associated mild demyelination which may vary in severity within the same family. Clinical diagnosis was more difficult in this particular case due to the association with Parkinson symptoms.Neuromuscular Disorders 10/2014; 25(2). DOI:10.1016/j.nmd.2014.10.006 · 3.13 Impact Factor