In 2017, I completed my PhD studies at the University Complutense (UCM, Madrid, Spain) in the laboratory of Prof Miguel Diaz-Hernandez. The main objective of my PhD studies was to explore the role of purinergic signalling driven neuroinflammation in neurological disorders, in particular, how purinergic signalling-induced inflammation impacts on the functionality of the Ubiquitin-Proteasome System.
In 2018, I have been awarded a postdoctoral Marie-Sklodowska Curie Individual Fellowship (EpiBarrier 796600) at the Royal College of Surgeons (RCSI, Dublin, Ireland) with focus on the control of the blood-brain barrier integrity during seizures via the ATP-gated P2X7 receptor under the supervision of Dr Tobias Engel.
Over the past decade, particular attention has been paid to dysfunction of cerebral vasculature and inflammatory processes as important players in epileptogenic processes, with a specific emphasis on failure of the blood–brain barrier (BBB). A functional BBB is crucial in maintaining brain homeostasis and to prevent the entry of toxic compounds and immune cells into the Central Nervous System.
Leakage of the BBB is one of the earliest characteristic pathophysiological disturbances following status epilepticus and may play an important role in the development of epilepsy. The purinergic ATP-gated P2X7 receptor has gained much attention as a novel target in the treatment of epilepsy. Moreover, P2X7 has been associated with numerous damaging processes related to epileptogenesis, such as inflammation and opening of the BBB.
ATP and the P2X7 downstream target Interleukin-1β contribute to the disruption of the BBB and P2X7 antagonism protects against BBB disruption during intracerebral haemorrhage. To date, however, we do not know whether seizure induced changes of the BBB are dependent on P2X7 signalling.
Therefore, our research aim is to test whether P2X7 signalling contributes to BBB opening during seizures and epilepsy and whether P2X7 antagonism counteracts BBB disruption thereby reducing seizure severity and the development of epilepsy.
“ATP Measurement in Cerebrospinal Fluid Using a Microplate Reader” de Diego-García L, Sebastián-Serrano A, Bianchi C, Di Lauro C, Díaz-Hernández M. Methods Mol Biol. 2020;2041:233-241. Link to paper here.
“Context-specific switch from anti- to pro-epileptogenic function of the P2Y1 receptor in experimental epilepsy” Alves M, de Diego-García L, Conte G, Jimenez-Mateos EM, D’orsi B, Sanz-Rodriguez A, Prehn J, Henshall D, Engel T; J Neurosci. 2019 Jul 3;39(27):5377-5392. Link to paper here.
“Amyloid peptide-induced neuroinflammation causes changes on P2X7R distribution pattern impacting on microglial cell functionality” Martínez-Frailes C, Di Lauro C, Bianchi C, de Diego-García L, Sebastián-Serrano A, Bosca L, Díaz-Hernández M; Front Cell Neurosci. 2019 Apr 12;13:143. Link to paper here.
“Nucleotides regulate the common molecular mechanisms that underlie neurodegenerative diseases; therapeutic implications” Sebastián-Serrano A, de Diego-García L, Di Lauro C, Bianchi C, Díaz-Hernández M. Brain Res Bull. 2019 Sep; 151:84-91; Review. Link to paper here.
“The Neurotoxic Role of Extracellular Tau Protein” Sebastián-Serrano A; de Diego-García L, Díaz-Hernández M. International Journal of Molecular Sciences. 2018 Mar 27; 19(4); Review. Link to paper here.
“Haploinsufficient TNAP mice display decreased extracelular ATP levels and expression of Pannexin-1 channels” Sebastián-Serrano A; de Diego-García L, Hensall DC, Engel T, Díaz-Hernández M. Frontiers in Pharmacology. 2018 Mar 2; 9:170. Link to paper here.
“The regulation of proteostasis in glial cells by nucleotide receptors is key in acute neuroinflammation” de Diego-García L, Sebastián-Serrano A, Hernández IH, Pintor J, Lucas JJ, Díaz-Hernández M. FASEB J 2018 Jun;32(6):3020-3032. Link to paper here.
“Neuronal P2X7 receptor: involvement in neuronal physiology and pathology” Miras-Portugal MT, Sebastián-Serrano A, de Diego-García L, Díaz-Hernández M. Journal of Neuroscience. 2017 Jul 26; 37(30):7063-7072. Link to paper here.
“Regulation of proteasome activity by P2Y2 receptor underlies the neuroprotective effects of extracelular nucleotides” de Diego-García L, Ramírez-Escudero M, Sebastián-Serrano Á, Diaz-Hernández JI, Pintor J, Lucas JJ, Díaz-Hernández M. Biochim Biophys Acta. 2017 Jan;1863(1):43-51. Link to paper here.
“Neurodevelopmental alterations and seizures developed by mouse model of infantile hypophosphatasia are associated with purinergic signalling deregulation” Sebastián-Serrano Á, Engel T, de Diego-García L, Olivos-Oré LA, Arribas-Blázquez M, Martínez-Frailes C, Pérez-Díaz C, Millán JL, Artalejo AR, Miras-Portugal MT, Henshall DC, Díaz-Hernández M. Hum Mol Genet. 2016 Oct 1; 25 (19):4143-4156. Link to paper here.
“Tissue-nonspecific Alkaline Phosphatase Regulates Purinergic Transmission in the Central Nervous System During Development and Disease” Sebastián-Serrano Á, de Diego-García L, Martínez-Frailes C, Ávila J, Zimmermann H, Millán JL, Miras-Portugal MT, Díaz-Hernández M. Comput Struct Biotechnol J. 2014 Dec 15;13:95-100. Link to paper here.