Insufficient Cellular Recycling Behind Rare Neurodevelopmental Disorder

NIH scientists have discovered a new neurodevelopmental disorder that they have associated with pathogenic variants in genes encoding autophagy-related proteins. The rare neurological disease was found in three children that all had issues with motor coordination and speech, as well as mutations in both copies of the ATG4D gene.

ATG4D aids in autophagy, which cells use to break down and recycle damaged proteins and other defective pieces of the cell to stay healthy. Autophagy is a fundamental process used by cells throughout the body, but neurons are particularly dependent on autophagy for survival. However, little is known about how ATG4D contributes to healthy neurons.

The first inclination of ATG4D’s effects on brain health came from a 2015 study in which researchers identified a genetic neurological disease among Lagotto Romagnolo dogs, an Italian breed known for their fluffy coats and truffle-hunting abilities. The affected dogs had abnormal behavior, atrophy of the cerebellum, issues with motor coordination and eye movement and ATG4D mutations. While this 2015 study invigorated research interest in ATG4D’s role in the brain, scientists had yet to connect ATG4D to any neurological disease in humans.

“Among genetic diseases, we’ve solved many of the lower hanging fruits,” said May Christine Malicdan, senior author of the study published in Genomic Medicine. “Now, we’re reaching for the higher fruits—genes like ATG4D that are more difficult to analyze—and we have the genomic and cellular tools to do so.”

Computational analyses predicted that the three children’s ATG4D mutations would produce dysfunctional proteins. However, three other genes in the human genome serve very similar roles to ATG4D, and in some cells, these other genes may compensate for a loss of ATG4D.

While all cells in the body share the same genome, some genes are more important for certain cells. When the researchers studied the children’s ATG4D mutations in skin cells, the variants did not affect the cells’ recycling process, but this may not be true in the brain. “The brain is so complex, and neurons have very specialized functions. To fit those functions, different neurons use different genes, so changes in redundant genes can have major impacts in the brain,” said Malicdan.

To simulate cells that rely more heavily on ATG4D, the researchers deleted the similar genes in cells grown in the laboratory and then inserted the children’s ATG4D mutations. The researchers determined the cells with the children’s ATG4D mutations could not carry out the necessary steps for autophagy, indicating that the children’s symptoms are likely caused by insufficient cellular recycling.