Molecular pathogenesis of seipin/BSCL-2-related motor neuron diseases. Ann Neurol 61: 237-250

Department of Neurology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
Annals of Neurology (Impact Factor: 9.98). 03/2007; 61(3):237-50. DOI: 10.1002/ana.21070
Source: PubMed


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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    • "Several ER-Golgi transport proteins are implicated in other motor neuron disorders, including atlastin (Botzolakis et al. 2011) and seipin (Ito and Suzuki 2007). Furthermore, disruption in ER-Golgi trafficking has also been described in spontaneous mouse mutants with motor phenotypes, pmn (Schaefer et al. 2007) and wobbler (Schmitt-John et al. 2005). "
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    ABSTRACT: Cu/Zn-superoxide dismutase (SOD1) is misfolded in familial and sporadic Amyotrophic Lateral Sclerosis (ALS), but it is not clear how this triggers endoplasmic reticulum (ER) stress or other pathogenic processes. Here we demonstrate that mutant SOD1 (mSOD1) is predominantly found in the cytoplasm in neuronal cells. Furthermore, we show that mSOD1 inhibits secretory protein transport from the ER to Golgi apparatus. ER-Golgi transport is linked to ER stress, Golgi fragmentation and axonal transport and we also show that inhibition of ER-Golgi trafficking preceded ER stress, Golgi fragmentation, protein aggregation and apoptosis in cells expressing mSOD1. Restoration of ER-Golgi transport by over-expression of coatomer coat protein II (COPII) subunit Sar1 protected against inclusion formation and apoptosis, thus linking dysfunction in ER-Golgi transport to cellular pathology. These findings thus link several cellular events in ALS into a single mechanism occurring early in mSOD1 expressing cells. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 10/2013; 129(1). DOI:10.1111/jnc.12493 · 4.28 Impact Factor
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    • "After extensive washing in PBS slides were processed for immunofluorescent histochemical detection of seipin. Slides were incubated in blocking buffer containing 0.5% BSA, 0.5% Triton-X 100 in PBS for 1 hr at room temperature and then incubated overnight at room temperature in blocking buffer containing rabbit anti-seipin antibody (1/1000; [20]). Sections were subsequently washed in PBS followed by incubation with a donkey anti-rabbit 488 antibody (1/1000 in blocking buffer, Alexa Fluor, Molecular Probes) for 1 hr at room temperature. "
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    ABSTRACT: The endoplasmic reticulum localised protein seipin, encoded by the gene Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), serves a critical but poorly defined function in the physiology of both adipose and neural tissue. In humans, BSCL2 loss-of-function mutations cause a severe form of lipodystrophy, whilst a distinct set of gain-of-toxic-function mutations are associated with a heterogeneous group of neuropathies. However, despite the importance of seipin dysfunction to the pathophysiology of these conditions, little is known about its physiological role in adipocytes or neurons. BSCL2 mRNA has previously been identified in human and mouse brain, yet no definitive assessment of its expression has been undertaken. Here we comprehensively characterised the neuroanatomical distribution of mouse Bscl2 using complementary in situ hybridisation histochemistry and immunohistochemistry techniques. Whilst Bscl2 was broadly expressed throughout the rostral-caudal extent of the mouse brain, it exhibited a discrete neuroanatomical profile. Bscl2 was most abundantly expressed in the hypothalamus and in particular regions associated with the regulation of energy balance including, the paraventricular, ventromedial, arcuate and dorsomedial nuclei. Bscl2 expression was also identified within the brainstem dorsal vagal complex, which together with the paraventricular nucleus of the hypothalamus represented the site of highest expression. Further neurochemical profiling of these two nuclei revealed Bscl2/seipin expression within energy balance related neuronal populations. Specifically, seipin was detected in oxytocin neurons of the paraventricular nucleus of the hypothalamus and in catecholamine neurons of the dorsal vagal complex. These data raise the possibility that in addition to its role in adipose tissue development, seipin may also be involved in the central regulation of energy balance.
    PLoS ONE 09/2012; 7(9):e45790. DOI:10.1371/journal.pone.0045790 · 3.23 Impact Factor
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    • "These amino acid supstitutions affect glycosylation of seipin and result in accumulation of unfolded mutant seipin in the endoplasmatic reticulum (ER) [9]. Expression of mutant seipin increases the level of ER stress-mediated molecules and induces apoptosis leading to neurodegeneration [9]. The range of phenotypic manifestations in mutation carriers varied from asymptomatic individuals to severely affected patients showing either a dHMN type V or Silver syndrome phenotype [3]. "
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    ABSTRACT: Distal hereditary motor neuropathy type V (dHMN-V) and Silver syndrome are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene or Seipin. To report the first Serbian family with a BSCL2 mutation showing variable expression within the family. A 55-year-old woman presented with weakness of both hands at the age of 45. At age 47, she noticed distal muscle weakness and atrophy in her legs. Physical examination revealed atrophy and weakness of small hand muscles and mild atrophy and weakness of the lower limbs. There was generalized hyperreflexia with the exception of ankle reflexes which were diminished. Her 25year-old son had only stiffness of both legs at the age of 22. Physical examination revealed only generalized hyporeflexia. The third affected member in this family was her 55year-old cousin who showed a more prominent involvement of leg muscles with mild asymmetrical weakness of hand muscles and no pyramidal tract features. In all three patients sensory nerve conduction velocities (NCV) were normal in all extremities. Compound muscle action potential (CMAP) amplitudes were markedly reduced in all patients. Concentric needle EMG showed evidence of chronic denervation in distal muscles. DNA sequencing of BSCL2 was performed and a heterozygous N88S missense mutation in BSCL2 gene was detected in all three patients. This report is further confirmation of phenotypic heterogenity due to the N88S mutation of BSCL2 gene in the same family.
    Journal of the neurological sciences 09/2010; 296(1-2):107-9. DOI:10.1016/j.jns.2010.06.015 · 2.47 Impact Factor
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