Ph.D Thesis

Ph.D StudentKolodney Goren
SubjectApoptotic Dysregulation of D-Serine Dynamics: Implications
for Neurodegeneration
DepartmentDepartment of Medicine
Supervisor PROF. Herman Wolosker
Full Thesis textFull thesis text - English Version


D-serine is a physiological co-agonist at N-methyl D-aspartate receptors (NMDARs) and is essential for neurotransmission, synaptic plasticity and behavior. D-serine also mediates NMDAR-mediated neurotoxicity, suggesting that it plays a role in neurodegeneration. Synthesis of D-serine is carried out by the enzyme serine racemase (SR), which directly converts L- to D-serine. Despite the plethora of roles attributed to D-serine, little is known regarding its regulation in physiological and pathological conditions. In this study we examine mechanisms regulating D-serine synthesis by the enzyme SR, in pathological settings, relevant for neurodegeneration. We report that SR undergoes nucleocytoplasmic shuttling in primary cell cultures, and that this process is dys-regulated during neuronal apoptosis. Apoptotic stimuli promote significant nuclear accumulation of SR in proportion to stimuli duration, along with the nuclear translocation of GAPDH and Siah proteins. Likewise, mutation in putative SR nuclear export signals (NES's) promotes SR nuclear accumulation and its depletion from the cytosol. In the nucleus, SR appears to be strongly bound to the nuclear cytoskeleton, where it co-localizes with the cytoskeletal protein Lamin. Nuclear translocation completely abolishes SR activity rendering SR inactive towards D-serine synthesis. This process provides a novel feedback inhibition mechanism that might prevent NMDAR over-activation in nearby synapses by curbing D-serine synthesis and thus may avert the demise of vicinal neurons following acute ischemic injury or neurodegeneration known to involve NMDAR toxicity.