Abstract
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.
Highlights
Macroautophagy, referred to hereafter as autophagy, is a cellular process by which proteins and organelles are degraded and recycled through sequestration within autophagosomes and delivery to lysosomes (Levine and Klionsky, 2004)
Comparison of protein isolated from control lymphoblastoid cell lines (LCL) and of affected subjects revealed a severe reduction of the ATG12–ATG5 conjugate in the mutant cells under basal conditions (Figure 3A), suggesting that the E122D mutation may have impaired autophagy by inhibiting conjugation between ATG12 and ATG5
We demonstrate that the homozygous E122D mutation of ATG5, a unique mutation found in two human subjects with ataxia, results in reduced conjugation to ATG12 and in an overall decrease in autophagy activity
Summary
Macroautophagy, referred to hereafter as autophagy, is a cellular process by which proteins and organelles are degraded and recycled through sequestration within autophagosomes and delivery to lysosomes (Levine and Klionsky, 2004). The autophagy pathway is highly conserved and required for organismal development and function. Defects in autophagy are associated with diseases including cancer, metabolic disruption, and neurodegenerative disorder Human biology and medicine Neuroscience eLife digest Ataxia is a rare disease that affects balance and co-ordination, leading to difficulties in walking and other movements. The disease mostly affects adults, but some children are born with it and they often have additional cognitive and developmental problems. Mutations in at least 60 genes are known to be able to cause ataxia, but it is thought that there are still more to be found
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