Genetic and biochemical determinants of brain calcification

Brain calcification can cause movement disorders and cognitive impairment. Researchers have now identified a gene that provides new insight into how these calcifications occur.

"Calcifications are often associated with disease states in joints or blood vessels, but it is actually also very common in the brain. Brain calcification is however less well studied", says the researcher.

The researchers have taken a closer look at a specific type of brain calcification, called primary familial brain calcification (PFBC, formerly called Fahr's disease). In this rare neurodegenerative condition, progressive muscular symptoms, psychiatric symptoms and cognitive impairment occur:

"This condition is caused by pathogenic, meaning disease-causing, gene variants and entail particularly severe brain calcification", says the author.

PFBC can be caused by mutations in various genes, and researchers are working to find out which ones. Now, through an international collaboration, the research group discovered a new gene that can be linked to this disease.

The Lab has expertise in the novel PFBC gene, NAA60. "PFBC is a very favorable model for studying brain calcifications", the author explains.

Among those with a PFBC diagnosis, errors are found in various genes. There were six genes linked to the disease before the research group's work.

"Since defects in different genes cause the same disease, this indicates which molecular players are involved in the calcification process", the senior author explains.

"By adding NAA60 to the list as the seventh gene that can cause PFBC, and linking this with our previous work, we have made a big step towards being able to explain how calcification can develop in the brain", the author continues.

"During the last few years, a large international collaboration took form, to together describe a total of six different NAA60 mutations, found in ten individuals from seven families, now presented in this article", says the author.

Since half of those currently diagnosed with PFBC do not have a genetic explanation, it is assumed that NAA60 may be behind additional cases. The work has now been published in the scientific journal Nature Communications.

"The recently published article presents the new gene link and shows that the mutations cause loss of NAA60 function", says the author.

The loss of function manifests itself in a lack of the NAA60 protein with lack of protein N-terminal (Nt)-acetylation activity that is normally expressed through the gene.

The researchers also show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. 

"But there is still a lot of work to be done to understand the molecular processes that can explain how a lack of the NAA60 protein leads to brain disease", says the researcher.