title: Contribution of serine racemase/d-serine pathway to neuronal apoptosis.
abstract: Recent data indicate that age-related N-methyl-d-aspartate receptor (NMDAR) transmission impairment is correlated with the reduction in serine racemase (SR) expression and d-serine content. As apoptosis is associated with several diseases and conditions that generally occur with age, we investigated the modulation of SR/d-serine pathway during neuronal apoptosis and its impact on survival. We found that in cerebellar granule neurons (CGNs), undergoing apoptosis SR/d-serine pathway is crucially regulated. In the early phase of apoptosis, the expression of SR is reduced, both at the protein and RNA level through pathways, upstream of caspase activation, involving ubiquitin proteasome system (UPS) and c-Jun N-terminal kinases (JNKs). Forced expression of SR, together with treatment with NMDA and d-serine, blocks neuronal death, whereas pharmacological inhibition and Sh-RNA-mediated suppression of endogenous SR exacerbate neuronal death. In the late phase of apoptosis, the increased expression of SR contribute to the last, NMDAR-mediated, wave of cell death. These findings are relevant to our understanding of neuronal apoptosis and NMDAR activity regulation, raising further questions as to the role of SR/d-serine in those neuro-pathophysiological processes, such as aging and neurodegenerative diseases characterized by a convergence of apoptotic mechanisms and NMDAR dysfunction.
authors.affiliation: Istituto di Biologia Cellulare e Neurobiologia, CNR, Roma, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Esposito
authors.forename: Andrea
authors.initials: A
authors.lastname: Pristerà
authors.forename: Giovanna
authors.initials: G
authors.lastname: Maresca
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Cavallaro
authors.forename: Armando
authors.initials: A
authors.lastname: Felsani
authors.forename: Fulvio
authors.initials: F
authors.lastname: Florenzano
authors.forename: Luigi
authors.initials: L
authors.lastname: Manni
authors.forename: Maria T
authors.initials: MT
authors.lastname: Ciotti
authors.forename: Loredano
authors.initials: L
authors.lastname: Pollegioni
authors.forename: Tiziana
authors.initials: T
authors.lastname: Borsello
authors.forename: Nadia
authors.initials: N
authors.lastname: Canu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012694:Serine / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013237:Stereoisomerism; D000099300:Serine Racemase
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D000099300:Serine Racemase