Serina racemase, neuropathologies and psychiatric disorders

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The relevance of NMDAR in mediating relevant biological events, including NMDAR neurotransmission (84), synaptic plasticity (85), cell migration (66) and long term potentiation (86) is well established. The involvement of NMDAR signals in neurotoxicity and associated apoptotic events as well as psychiatric diseases is also well established (8, 81, 87-89). High and low D-serine levels cause distinct neuropathologies and aging-related deficits (90), mediated by hyper- and hypo-activation of NMDAR, respectively. To the onset of neurological disorders, studies seems to indicate that the cellular levels of D-serine are not directly related with the levels of SR transcription (70, 90, 94). Thus, only a detailed elucidation of the molecular basis of the complex disease-triggering mechanisms and SR can open the way to tailored therapeutic treatments.

Schizophrenia

This psychiatric disorder causes many behavioural effects and cognitive deficits and has been linked to low NMDAR activity. There are many causes, ranging from intrinsic receptor abnormalities to inefficient receptor regulation (89). Furthermore, low levels of SR and low concentration of D-serine (76, 91, 92), caused by high levels of DAAO (93, 94), have been linked to schizophrenia (76). However, some studies rule out a genetic association between schizophrenia and serine racemase (95). It was also demonstrated in mice that the conditional deletion of D-3-phosphoglycerate dehydrogenase, the enzyme that catalyzes the first step in L-serine synthesis via the phosphorylated pathway, causes a significant decrease of both L- and D-serine with no effect on the expression level of SR (96). The interaction between SR and DISC1, described above, seems consistent with a role of SR in the pathophysiology of the disease. PICK1, another SR interactor, has also been linked to schizophrenia (68, 69).

Amyotrophic lateral sclerosis

This disease causes a dramatic loss of motor neurons in the spinal cord and brain leading to paralysis. The consensus hypothesis is that amyotrophic lateral sclerosis (ALS) pathogenesis is due to excitotoxicity mediated by ionotropic glutamate receptors, namely NMDAR, AMPAR and kainate receptor. Specifically, neuronal death is triggered by over-activation of NMDAR caused by high levels of D-serine (97). A recent study has demonstrated that DAAO inactivation is responsible for high levels of D-serine (98). Furthermore, it was observed that D-serine levels are two-fold higher in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice, the model of ALS (99). ALS mice deprived of SR show earlier symptoms onset of the disease, but the progression phase is slowed and dependent on SR. Surprisingly, administration of D-serine to ALS mice dramatically lowers cord levels of D-serine, leading to changes in ALS onset and survival very similar to SR deletion. It was also found that D-serine treatment causes an increase of cord levels of the alanine–serine–cysteine transporter 1 (Asc-1). The mechanism linking SOD1 mutations to increased D-serine levels is not known. However, these results suggest that SR and D-serine are involved in both the pre-symptomatic and progression phases of ALS (99).

Alzheimer’s disease

This disease causes a global progressive impairment of mental functions resulting from many and not yet fully understood mechanisms. It was reported that NMDARs significantly decrease in selected brain regions of Alzheimer’s disease (AD) patients (100). However, NMDAR activity is higher in AD and memantine, a drug that acts as an antagonist of NMDAR, is able to ameliorate the clinical pattern (101, 102). These findings point to a role of overactivated NMDARs in AD pathophysiology. In AD patients, SR activity is higher in the hippocampus (103) and D-serine levels are increased in the cerebrospinal fluid (104). Furthermore, amyloid b-peptides, the hallmark of AD, stimulate in vivo the synthesis and release of D-serine (103).

Other neurodegenerative diseases, such as Parkinson and Huntington, have been associated with hyperactivation of NMDAR and with high concentrations of D-serine, resulting from high levels of SR activity and low levels of DAAO activity (81).

Stroke/ischemia

Excitotoxic signals originate from lack of oxygen, followed by tissue reperfusion. These events are associated with cell death pathways triggered by overactivated NMDAR that are prevented by agents blocking NMDAR activity, such as memantine (81, 102). High levels of D-serine are observed in simulated ischemia models, causing neuronal death (105). Consequently, a protective effect towards ischemic neurotoxicity was observed in SR-depleted cultures of brain mice where a reduced formation of NO and NO-triggered events was observed (106).