LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans.

Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here, we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.

mRNA decapping is an evolutionarily conserved modulator of neuroendocrine signaling that controls development and ageing.

Eukaryotic 5'-3' mRNA decay plays important roles during development and in response to stress, regulating gene expression post-transcriptionally. In Caenorhabditis elegans, deficiency of DCAP-1/DCP1, the essential co-factor of the major cytoplasmic mRNA decapping enzyme, impacts normal development, stress survival and ageing. Here, we show that overexpression of dcap-1 in neurons of worms is sufficient to increase lifespan through the function of the insulin/IGF-like signaling and its effector DAF-16/FOXO transcription factor. Neuronal DCAP-1 affects basal levels of INS-7, an ageing-related insulin-like peptide, which acts in the intestine to determine lifespan. Short-lived dcap-1 mutants exhibit a neurosecretion-dependent upregulation of intestinal ins-7 transcription, and diminished nuclear localization of DAF-16/FOXO. Moreover, neuronal overexpression of DCP1 in Drosophila melanogaster confers longevity in adults, while neuronal DCP1 deficiency shortens lifespan and affects wing morphogenesis, cell non-autonomously. Our genetic analysis in two model-organisms suggests a critical and conserved function of DCAP-1/DCP1 in developmental events and lifespan modulation.

New mutations and genotype-phenotype correlation in late-onset Pompe patients.

Pompe disease is a glycogen storage disease caused by acid alfa-glucosidase deficiency. Here, we report clinical properties, genetic features of our late-onset Pompe patients. Seven patients were followed during the last 10 years in our institute. The clinical and laboratory findings were reviewed. Neuropsychological evaluation was performed in four patients. Myotonic discharges of paraspinal muscles and denervation potentials were seen in all patients at the diagnosis and were disappeared during follow-up in two. Only one patient, whose MRI showed cerebral atrophy, had attention and executive dysfunction. Compound heterozygous patients with IVS 1-13T>G have a milder disease. One patient who has homozygous IVS 1-13T>G mutation had more severe disease. Two of our patients who had very severe and fatal disease course carry double mutations on both alleles (c.547-39T>G and c.858+5ins7) that previously scored as "unknown" in Erasmus Pompe Center database. Lastly, we found new mutations (c.1209 C>A, 2737dupG) in two patients carrying IVS 1-13T>G in the other allele. Systemic involvements are very rare in late-onset Pompe patients. Similarly, Pompe disease does not cause cognitive impairment in adult population. Homozygous IVS 1-13T>G mutation and c.547-39T>G mutation which are previously noted as "unknown" pathogenicities cause a more severe disease.