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

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.DOI: http://dx.doi.org/10.7554/eLife.12245.001

Therapeutic Targeting of Autophagy

“…Moreover, when Atg7 is acutely deleted in all cells in adult animals, the most common cause of death is neurodegenerative disease with accumulation of ubiquitinated protein aggregates (Karsli-Uzunbas et al, 2014). A mutation in the human ATG5 gene that inhibits autophagy also causes congenital ataxia and developmental delay (Kim et al, 2016). The second link to neurodegenerative diseases including Alzheimers Disease (AD), Parkinson's Disease (PD), and Huntington's Disease (HD) is the involvement of toxic protein aggregates that can be degraded via autophagy in the pathology of all of these diseases (Nah et al, 2015).…”

Autophagy wins the 2016 Nobel Prize in Physiology or Medicine: Breakthroughs in baker's yeast fuel advances in biomedical research

“…These roles stem from the ability of autophagy to degrade unwanted or harmful substrates (largely via selective autophagy), to recycle cytoplasmic constituents during environmental stress (largely through nonselective autophagy), and from other homeostatic functions of the autophagy machinery. Importantly, it is now clear that mutations in genes encoding core components that are required for autophagosome formation are associated with human disease (51,52).…”

Autophagy core machinery: overcoming spatial barriers in neurons

“…Even seemingly nuanced mutations can lead to neuronal dysfunction. For example, a single mutation in a core member of the autophagic machinery has been identified as the cause of ataxia in patients with severe neurological abnormalities [78, 79]; an E122D mutation in ATG5 results in ineffective conjugation to ATG12 and, thus, overall decreases the level of autophagy in both mammalian and yeast model systems [79]. …”