New insights into physiology of aged-related cognitive disorders: the DNA repair protein ATR

Aging is a multifactorial process characterized by the slow decline of cellular physiology associated with a lowdown of brain functions (1,2). Neurological complications mainly reflect defects at the synaptic structure. Indeed, preclinical studies demonstrate that preserving functionality of synapses delays the occurrence of aged-related neurological and cognitive defects and prevents the progressive neuronal degeneration (3). Since defects in DNA repair mechanisms have a critical role in aged-related neurological diseases (4,5,6,7) and expression of core DNA repair genes is downregulated during aging across brain regions (8), we are investigating the impact of ATR (Ataxia Telangiectasia mutated-Rad3 related) protein, a kinase activated primarly by DNA damage, in synapse physiology and its potential role in aging neuropathology. Whereas in literature it has been reported that ATR deletion leads to the calcium sensor synaptotagmin2 (SYT2) upregulation at excitatory neurons conferring hyperexcitability (9), our electrophysiological and confocal studies indicate in wt neurons treated with a ATR kinase activity inhibitor higher inhibition. Thus, diverse phenotypes result from the genetic deletion or pharmacological inactivation of ATR kinase activity. Also, the specific block of ATR prevents the induction of long-term potentiation upon glycine stimulation in neurons suggesting impaired NMDA-mediated processes. Indeed, calcium imaging recordings confirmed reduced calcium elevations in neurons with impaired ATR kinase activity upon transient exposure to exogenous NMDA. Our data indicate that activity of ATR is essential to synapse functionality and that alterations in its activation may affect neuronal health beyond its expected responses to DNA damages and oxidative stress.