Autophagy is a degradation process of cytoplasmic cellular constituents, which serves as a survival mechanism in starving cells, and it is characterized by sequestration of bulk cytoplasm and organelles in double-membrane vesicles called autophagosomes. Autophagy has been linked to a variety of pathological processes such as neurodegenerative diseases and tumorigenesis, which highlights its biological and medical importance. We have previously characterized the vacuole membrane protein 1 (VMP1) gene, which is highly activated in acute pancreatitis, a disease associated with morphological changes resembling autophagy. Here we show that VMP1 expression triggers autophagy in mammalian cells. VMP1 expression induces the formation of ultrastructural features of autophagy and recruitment of the microtubule-associated protein 1 light-chain 3 (LC3), which is inhibited after treatment with the autophagy inhibitor 3-methiladenine. VMP1 is induced by starvation and rapamycin treatments. Its expression is necessary for autophagy, because VMP1 small interfering RNA inhibits autophagosome formation under both autophagic stimuli. VMP1 is a transmembrane protein that co-localizes with LC3, a marker of the autophagosomes. It interacts with Beclin 1, a mammalian autophagy initiator, through the VMP1-Atg domain, which is essential for autophagosome formation. VMP1 endogenous expression colocalizes with LC3 in pancreas tissue undergoing pancreatitisinduced autophagy. Finally, VMP1 stable expression targeted to pancreas acinar cell in transgenic mice induces autophagosome formation. Our results identify VMP1 as a novel autophagy-related membrane protein involved in the initial steps of the mammalian cell autophagic process.Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents, which serves as a survival mechanism in starving cells (1-3). This catabolic process is involved in the turnover of long lived proteins and other cellular macromolecules, and it might play a protective role in development, aging, cell death, and defense against intracellular pathogens (4 -8). By morphological studies, autophagy has been linked to a variety of pathological processes such as neurodegenerative diseases and tumorigenesis, which highlights its biological and medical importance (4, 9, 10). Early reports of autophagy in human disease include the ultrastructural autophagic features described in pancreas from human pancreatitis (11,12).Autophagy is characterized by sequestration of bulk cytoplasm and organelles in double-membrane vesicles called autophagosomes, which eventually acquire lysosomal-like features (13,14). Autophagy is mediated by a set of evolutionarily conserved gene products (termed the Atg proteins) originally discovered in yeast (15). In mammalian cells, Beclin 1 (3, 16 -18) promotes autophagosome formation when it functions as part of a complex with the Class III phosphatidylinositol 3-kinase (PI3K) 6 mediating the localization of other autophagic proteins to the autophagosomal membrane (19)...

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Objective: We investigated mitochondrial DNA (mtDNA) variants in children with a first episode of acquired demyelinating syndromes (PD-ADS) of the CNS and their relationship to disease phenotype, including subsequent diagnosis of multiple sclerosis (MS).Methods: This exploratory analysis included the initial 213 children with PD-ADS in the prospective Canadian Pediatric Demyelinating Study and 166 matched healthy sibling controls from the Canadian Autism Genome Project. A total of 31 single nucleotide polymorphisms (SNPs) were analyzed, including haplogroup-defining SNPs and mtDNA variants previously reported to be associated with MS. Results: Primary Leber hereditary optic neuropathy (LHON) mutations and other known patho-genic mtDNA mutations were absent in both patients with pediatric acquired demyelinating syndromes and controls. The 13708A haplogroup J-associated variant, previously linked to adult MS, was more frequent among subjects with PD-ADS (13.0%) compared to controls (6.2%; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.06 to 4.83) and haplogroup M was associated with an earlier age at onset of PD-ADS (Ϫ1.74 years; 95% CI Ϫ3.33 to Ϫ0.07). In contrast, the haplogroup cluster UKJT, as well as 3 other SNPs, were each associated with a lower risk of PD-ADS. A total of 33 subjects with PD-ADS were diagnosed with MS during a mean follow-up period of 3.11 Ϯ 1.14 (SD) years. No single SNP was associated with the risk of subsequent diagnosis of MS. However, haplogroup H was associated with an increased risk of MS (OR 2.60; 95% CI 1.21 to 5.55). Conclusion:These data suggest an association between mtDNA variants and the risk of PD-ADS and of a subsequent MS diagnosis. Replication of these findings in an independent population of subjects with PD-ADS is required. Neurology ® 2011;76:774-780 GLOSSARY ADEM ϭ acute disseminated encephalomyelitis; ADS ϭ acquired demyelinating syndrome; CI ϭ confidence interval; LHON ϭ Leber hereditary optic neuropathy; MS ϭ multiple sclerosis; mtDNA ϭ mitochondrial DNA; OR ϭ odds ratio; PD-ADS ϭ first episode of acquired demyelinating syndrome; SNP ϭ single nucleotide polymorphism.

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