ATG4D assists in the autophagy process, which cells utilise to digest and recycle harmed proteins and other damaged parts of the cell to maintain health. Although all cells in the body use autophagy, neurons rely on it more than other cells do in order to survive. However, little is understood about the role ATG4D plays in maintaining healthy neurons.
An Italian breed of dogs noted for its fluffy coats and skill at finding truffles, the Lagotto Romagnolo, was found to have a hereditary neurological disorder in a 2015 study. This finding provided the first indication of the impact of ATG4D on brain health. ATG4D mutations, aberrant behaviour, cerebellar atrophy, problems with motor coordination and eye movement, and other symptoms were present in the affected pups.
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, M.D., Ph.D., NHGRI staff scientist and senior author of the study. "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.
Still, much about ATG4D remains unknown. "We have only a bird's eye view of many important cellular processes like autophagy," said Malicdan. A rare disease that involves changes in one gene can help tease apart how that gene acts in a broadly important cellular process.
Other components of autophagy are involved in common neurological disorders, such as Alzheimer's disease. Knowledge of this rare neurological disorder could lead to new avenues of research about ATG4D's involvement in more common conditions.
"That's the million-dollar question in rare disease research," said Malicdan. "Rare diseases can help us understand biological pathways, so we can better understand how those pathways contribute to other rare and common conditions."
NIH researchers and clinicians continue to work with the children in this study, and the researchers are aiming to identify more patients. Treatments are many steps away, but by learning more about ATG4D and autophagy, researchers may be able to develop new treatments for this condition and others involving autophagy pathways. (ANI)