HDAC Inhibitors as Epigenetic Regulators

Therefore,d-serine degradation by DAO in the reticulospinal tract is speculated to have a physiological significance in controlling motoneuronal excitability in rodents. to the lower motoneurons, predominantly contributes to thed-serine increase in the mSOD1 mouse. The DAO inactivity resulted from expressional down-regulation, which was reversed by inhibitors of a glutamate receptor and MEK, but not by those of inflammatory stimuli. Our findings provide evidence that DAO has a pivotal role in motoneuron degeneration throughd-serine regulation and that inactivity of DAO is a common feature between the mSOD1 ALS mouse model and the mutant DAO-associated familial ALS. The therapeutic benefit of reducingd-serine or controlling DAO activity in ALS should be tested in future studies. Keywords:excitotoxicity, motor neuron disease, neurodegeneration, enzyme histochemistry, 2D-HPLC Amyotrophic lateral sclerosis (ALS) ONX-0914 is a progressive neurodegenerative disorder characterized by selective loss of motoneurons in the spinal cord and brain leading to fatal paralysis. Approximately 90% of all cases are sporadic, and the remaining cases are inherited. Of inherited cases, 20% are associated with mutations in superoxide dismutase 1 (SOD1), and 10% involves 43-kDa transactivation ONX-0914 response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS). Despite extensive studies of previously identified ALS-causing genes, the mechanism underlying the selective motoneuronal loss in ALS remains uncertain. Given that the mechanism is at least, in part, common between sporadic and familial ALS, identification of the common pathology is a clue to conquering ALS. Among numerous etiological hypotheses, motoneuronal vulnerability to excitotoxicity is one of the most intensely investigated targets for the treatment of ALS because it is observed in both sporadic and familial ALS with SOD1 mutations (1,2). For motoneurons, glutamate is the main excitatory transmitter, and excessive motoneuron excitability by glutamate through ionotropic glutamate receptors has been demonstrated. TheN-methyl-d-aspartate (NMDA) receptor (NMDAR) is a subtype of the ionotropic glutamate receptors and exhibits relatively higher permeability to the calcium ion (Ca2+) than non-NMDARs, which links it to a variety of physiological and pathological processes. Unlike non-NMDARs, glutamate does not activate the NMDARs unless a coagonist binding site is occupied.d-Serine, an unusuald-amino acid found in mammalian brain, is a physiological ligand of the coagonist site of the NMDARs (3,4); hence, it is pivotal in determining excitability of glutamatergic neurons.d-Serine is endogenously converted froml-serine by serine racemase (SRR) (5) and exists at a high level in the forebrain, where it has a critical role in long-term potentiation (6) and is required for memory formation (6).d-Serine is also involved in NMDAR-mediated neurotoxicity, a process that ONX-0914 plays a pathophysiological role in stroke and neurodegenerative diseases (79). We previously reported thatd-serine is increased in the spinal cord in both patients with sporadic/familial ALS and in a G93A-SOD1 mouse model of ALS (mSOD1 mouse) (10).d-Serine is progressively increased with expressional elevation of SRR caused by glial activation (10). Intriguingly, a point mutation that diminishes enzyme activity ind-amino acid oxidase (DAO), ad-serine degrading enzyme, is associated with familial ALS (11). However, whether DAO is related tod-serine increase in ALS, or DAO inactivity is relevant to motoneuronal degeneration ONX-0914 in vivo, remains uncertain. In this study, we found that DAO activity is strikingly suppressed in the reticulospinal tract of mSOD1 mice, which plays a central role ind-serine increase in mSOD1 mice, and that loss of DAO activity results in motoneuron degeneration. == Results == DAO is highly expressed in mammalian CNS, liver, and ONX-0914 kidney and catalyzes the oxidative deamination ofd-amino acids. ddY/DAOmice, found in outbred ddY mice (12), lack DAO activity because of a natural point mutation (G181R) (13) and show abnormal SNF5L1 locomotor behavior related to enhanced NMDAR function (14). Because hypofunction of the NMDAR and genetic association of DAO have been implicated in schizophrenia, most studies using ddY/DAOmice have focused on a therapeutic approach to schizophrenia throughd-serine increase. No phenotypic analysis of spinal motoneurons in the mice, however, has yet been conducted. To study whether inactivation of DAO affects the motoneuronal phenotype in vivo, ddY/DAOmice were backcrossed with C57BL/6J and maintained as homozygotes (B6DAO/mice). TheB6DAO/mice developed an abnormal limb reflex characterized by retraction of hindlimbs toward the trunk when they were lifted up by their tails, whereas C57BL/6J mice showed normal extension of the hindlimbs (Fig. 1A). Motoneurons of the lumbar.