Serina racemase, neuropathologies and psychiatric disorders
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).
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