Open AccessContribution of serine racemase/ d ‐serine pathway to neuronal apoptosis
Author(s) -
Esposito Simona,
Pristerà Andrea,
Maresca Giovanna,
Cavallaro Sebastiano,
Felsani Armando,
Florenzano Fulvio,
Manni Luigi,
Ciotti Maria T.,
Pollegioni Loredano,
Borsello Tiziana,
Canu Nadia
Publication year - 2012
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2012.00822.x
Subject(s) - serine , biology , apoptosis , nmda receptor , microbiology and biotechnology , programmed cell death , neurodegeneration , receptor , signal transduction , neuroscience , biochemistry , phosphorylation , medicine , disease
Summary 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.