Dipartimento di Biotecnologie e Scienze Molecolari, Università degli studi dell'Insubria, via JH Dunant 3, 21100 Varese, Italy.
Mol Cell Neurosci. 2011 Sep;48(1):20-8. doi: 10.1016/j.mcn.2011.06.001. Epub 2011 Jun 12.
Accumulating genetic evidence indicates that the primate-specific gene locus G72/G30 is related to schizophrenia: it encodes for the protein pLG72, whose function is still the subject of controversy. We recently demonstrated that pLG72 negatively affects the activity of human d-amino acid oxidase (hDAAO, also related to schizophrenia susceptibility), which in neurons and (predominantly) in glia is expected to catabolize the neuromodulator d-serine. The d-serine regulation mechanism relying on hDAAO-pLG72 interaction does not match with the subcellular localizations proposed for hDAAO (peroxisomes) and pLG72 (mitochondria). By using glioblastoma U87 cells transfected with plasmids encoding for hDAAO and/or pLG72 we provide convergent lines of evidence that newly synthesized hDAAO, transitorily present in cytosol before being delivered to the peroxisomes, colocalizes and interacts with pLG72 which we propose to be exposed on the external membrane of mitochondria. We also report that newly synthesized cytosolic hDAAO is catalytically active, and therefore pLG72 binding-and ensuing hDAAO inactivation-plays a protective role against d-serine depletion.
越来越多的遗传证据表明，灵长类动物特异性基因座 G72/G30 与精神分裂症有关：它编码的蛋白 pLG72 其功能仍存在争议。我们最近证明，pLG72 会负向影响人 d-氨基酸氧化酶（hDAAO，也与精神分裂症易感性有关）的活性，而 hDAAO 在神经元中（主要）和神经胶质细胞中预期能分解神经调质 d-丝氨酸。依赖于 hDAAO-pLG72 相互作用的 d-丝氨酸调控机制与 hDAAO（过氧化物酶体）和 pLG72（线粒体）的亚细胞定位不符。通过转染含有 hDAAO 和/或 pLG72 编码质粒的神经胶质瘤 U87 细胞，我们提供了一致的证据，表明新合成的 hDAAO 短暂存在于细胞质中，然后被递送到过氧化物酶体，与我们提出存在于线粒体外膜上的 pLG72 共定位并相互作用。我们还报告说，新合成的细胞质 hDAAO 具有催化活性，因此 pLG72 结合并导致 hDAAO 失活，从而对 d-丝氨酸耗竭起到保护作用。
