Contribution of serine racemase/d‐serine pathway to neuronal apoptosis

Abstract

SummaryRecent 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.

Nuclear Compartmentalization of Serine Racemase Regulates d-Serine Production

“…Although we found no changes in total SR expression upon cell death insults, SR expression in cerebellar granule cells decreased during apoptosis (85). NMDAR activation was also shown to promote SR translocation from the cytosol to membranes, which also inhibits SR (29).…”

d-serine levels in Alzheimer’s disease: implications for novel biomarker development

“…d -serine administration has been shown to promote synaptogenesis and to have memory-enhancing effects. 25, 68, 69 Conversely, excessive d -serine levels were shown to mediate NMDAR-dependent late-phase apoptosis 70 and to contribute to neurological insults, such as excitotoxicity and brain ischemia. 22 Further, a recent report suggested that d -serine might act as a NMDAR antagonist under some circumstances.…”

Serine racemase: a key player in apoptosis and necrosis

“…Interestingly, a biphasic expression pattern for SR protein was observed, with a drastic drop in protein levels by 50 and 70% at 6 and 24 h after apoptosis induction, respectively, followed by a second wave of increased expression in the late phase of apoptosis. Such SR changes were not observed in glial cells, which account for only 1% of the total cells in culture (Esposito et al, 2012). The finding that a decrease in SR protein in CGNs undergoing apoptosis was accompanied by a reduction in intracellular D-serine levels gives support to the recent report that D-serine is predominantly produced by neuronal cells (Ehmsen et al, 2013).…”

“…Given that this condition was suggested to mirror the afferent glutammatergic inputs received by the CGNs in vivo (Borsello et al, 2000), it was hypothesized that NMDAR signaling ensures survival of newly generated granule neurons. It was then shown that NMDAR activation by exogenous NMDA prevented rat CGN survival from decreasing under low KCl concentrations (Balázs et al, 1988, 1989) by inhibiting programmed cell death (PCD) induced by low potassium levels (Yan et al, 1994; Alavez et al, 2006; Xifró et al, 2006; Bazán-Peregrino et al, 2007; Jantas and Lason, 2009; Esposito et al, 2012). Then, it was reported that NMDA offered protection to other neuronal populations in vitro , such as rat cortical neurons, subjected to several apoptotic stimuli, including serum deprivation and treatment with NMDAR antagonists or PI-3 kinase inhibitors (Hetman et al, 2000; Terro et al, 2000).…”

“…We, for the first time, have investigated whether the induction of the apoptotic program in a neuronal population—strongly dependent on NMDAR signaling for their survival and proper differentiation—induced a change in the enzymes related to D-serine metabolism, mainly SR (Esposito et al, 2012). …”