An all-Italian study indicates a new, possible, molecular mechanism that could cause the cognitive disorders and memory loss characteristic of Alzheimer’s and other forms of dementia. The study, conducted by researchers from the Istituto Superiore di Sanità, the Ircs San Raffaele Roma and the Cnr, reveals the role played by the DNA-Pkcs enzyme in stabilizing a protein responsible for the correct functioning of the synapses in our brain, and the mechanisms by which beta-amyloid plaques (considered by many to be the causal agent of Alzheimer’s) inhibit its action. The results, published in EMBO Reports, could pave the way for the development of new therapies and early diagnosis tools for the disease.
DNA-PKcs is a protein kinase involved in DNA repair mechanisms. In the brain, it is present inside the synapses, the point where neurons come into contact and exchange information with each other. It is known that in humans this enzyme plays a critical role in brain development, and that its functional alteration causes neurological deficits such as microcephaly and epilepsy.
For this reason, the authors of the new study decided to study in more depth the role that DNA-Pkcs plays inside the synapses. Their experiments have shown that it is responsible for the phosphorylation of the protein PSD-95, a molecule responsible for the organization of the synapses and the correct transmission of neural signals within them, which through this chemical modification is made stable and not susceptible to degradation.
Failure to repair DNA damage resulting from DNA-PKcs inhibition could therefore be implicated in the death of neurons observed in several neurodegenerative diseases, including Alzheimer’s. In fact, decreased levels of this enzyme have been observed in the past in the brains of patients with Alzheimer’s. In a 2016 study, the authors of the new research had already demonstrated that the beta-amyloid protein, among the main suspects as a possible primary cause of Alzheimer’s, is able to inhibit the activity of DNA-Pkcs.
“Therefore, this study proposes a new scenario in which in Alzheimer’s disease, but not only, the reduced enzymatic activity of DNA-PKcs, mediated by the accumulation of beta-amyloid, causes the reduction of PSD-95 levels in synapses due to its lack of phosphorylation, and consequently the dysfunction of the synapses. Which is at the basis of memory loss”, explains Daniela Merlo, Research Director of the Department of Neuroscience and Director of the Interdepartmental Structure on Dementia of the Istituto Superiore di Sanità and coordinator of the study. “The lack of phosphorylation of PSD-95 in neurodegenerative diseases characterized by cognitive deficit could represent a new biomarker for early diagnosis and monitoring of the disease over time”.
The ones discovered in the study are also molecular mechanisms that can be modified pharmacologically. And they could therefore become the target of new therapies in the future aimed at slowing down, or blocking, the brain damage that causes Alzheimer’s and other forms of dementia.