Characterization of the effects of age and childhood maltreatment on ELOVL2 DNA methylation.

DNA methylation of the elongation of very long chain fatty acids protein 2 (ELOVL2) was suggested as a biomarker of biological aging, while childhood maltreatment (CM) has been associated with accelerated biological aging. We investigated the association of age and CM experiences with ELOVL2 methylation in peripheral blood mononuclear cells (PBMC). Furthermore, we investigated ELOVL2 methylation in the umbilical cord blood mononuclear cells (UBMC) of newborns of mothers with and without CM. PBMC and UBMC were isolated from 113 mother-newborn dyads and genomic DNA was extracted. Mothers with and without CM experiences were recruited directly postpartum. Mass array spectrometry and pyrosequencing were used for methylation analyses of ELOVL2 intron 1, and exon 1 and 5' end, respectively. ELOVL2 5' end and intron 1 methylation increased with higher age but were not associated with CM experiences. On the contrary, overall ELOVL2 exon 1 methylation increased with higher CM, but these changes were minimal and did not increase with age. Maternal CM experiences and neonatal methylation of ELOVL2 intron 1 or exon 1 were not significantly correlated. Our study suggests region-specific effects of chronological age and experienced CM on ELOVL2 methylation and shows that the epigenetic biomarker for age within the ELOVL2 gene does not show accelerated biological aging years after CM exposure.

Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay.

Autophagy is required for the homeostasis of cellular material and is proposed to be involved in many aspects of health. Defects in the autophagy pathway have been observed in neurodegenerative disorders; however, no genetically-inherited pathogenic mutations in any of the core autophagy-related (ATG) genes have been reported in human patients to date. We identified a homozygous missense mutation, changing a conserved amino acid, in ATG5 in two siblings with congenital ataxia, mental retardation, and developmental delay. The subjects' cells display a decrease in autophagy flux and defects in conjugation of ATG12 to ATG5. The homologous mutation in yeast demonstrates a 30-50% reduction of induced autophagy. Flies in which Atg5 is substituted with the mutant human ATG5 exhibit severe movement disorder, in contrast to flies expressing the wild-type human protein. Our results demonstrate the critical role of autophagy in preventing neurological diseases and maintaining neuronal health.