Human genetics has indicated a causal role for the protein α-synuclein in the pathogenesis of familial Parkinson’s disease (PD), and the aggregation of synuclein in essentially all patients with PD suggests a central role for this protein in the sporadic disorder. Indeed, the accumulation of misfolded α-synuclein now defines multiple forms of neural degeneration. Like many of the proteins that accumulate in other neurodegenerative disorders, however, the normal function of synuclein remains poorly understood. α-Synuclein localizes specifically to the nerve terminal and inhibits neurotransmitter release when over-expressed, but the knockout has a modest effect on synaptic transmission, suggesting alternative presynaptic roles. Natively unstructured, synuclein adopts a helical conformation on membrane binding and recent work suggests a role in membrane remodeling. In neural degeneration, synuclein misfolds and aggregates as a β-sheet. Multiple observations now suggest propagation of the misfolded protein as a prion, providing a mechanism for the spread of degeneration through the neuraxis. However, the factors that trigger the original misfolding remain unknown.

Summary The protein α-synuclein has a central role in the pathogenesis of Parkinson’s disease (PD). Similar to other proteins that accumulate in neurodegenerative disease, however, the function of α-synuclein remains unknown. Localization to the nerve terminal suggests a role in neurotransmitter release and over-expression inhibits regulated exocytosis, but previous work has failed to identify a clear physiological defect in mice lacking all three synuclein isoforms. Using adrenal chromaffin cells and neurons, we now find that both over-expressed and endogenous synuclein serve to accelerate the kinetics of individual exocytotic events, promoting cargo discharge and reducing pore closure (‘kiss-and-run’). Thus, synuclein exerts dose-dependent effects on dilation of the exocytotic fusion pore. Remarkably, mutations that cause PD abrogate this property of α-synuclein without impairing its ability to inhibit exocytosis when over-expressed, indicating a selective defect in normal function.

SUMMARY Metabotropic glutamate receptor 5 (mGluR5) is highly expressed in the mammalian central nervous system (CNS). It is involved in multiple physiological functions and is a target for treatment of various CNS disorders, including schizophrenia. We report that Norbin, a neuron-specific protein, physically interacts with mGluR5 in vivo, increases the cell surface localization of the receptor and positively regulates mGluR5 signaling. Genetic deletion of Norbin attenuates mGluR5-dependent stable changes in synaptic function measured as long-term depression or long-term potentiation of synaptic transmission in the hippocampus. As with mGluR5 knockout mice or mice treated with mGluR5 selective antagonists, Norbin knockout mice showed a behavioral phenotype associated with a rodent model of schizophrenia, as indexed by alterations both in sensorimotor gating and psychotomimetic-induced locomotor activity.

SummaryAbnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, and depression. Adenosine, by activation of A 2A receptors, antagonizes dopamine signaling at D2 receptors and A 2A receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We report here a direct physical interaction between the G protein-coupled A 2A receptor and the receptor tyrosine kinase FGF receptor. Concomitant activation of these two classes of receptors, but not individual activation of either one alone, causes a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity induced by a novel A 2A R/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A 2A and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co-transmitter and open new avenues for therapeutic interventions.

Variations in the human mu-opioid receptor gene have driven exploration of their biochemical, physiological and pathological relevance. We investigated the existence of variations in the nonhuman primate mu-opioid receptor gene to determine whether nonhuman primates can model genotype/phenotype associations of relevance to humans. Similar to the A118G single nucleotide polymorphism (SNP) in the human mu-opioid receptor gene, a SNP discovered in the rhesus monkey mu-opioid receptor gene (C77G) alters an amino acid in the N-terminal arm of the receptor (arginine for proline at position 26). Two mu-opioid receptor coding regions isolated from a single heterozygous (C77/G77) rhesus monkey brain were expressed in HEK-293 cells and characterized in radioreceptor assays. Paralleling the findings of increased affinity of b-endorphin by the A118G allele in the human, the rhesus monkey mu-opioid receptor protein derived from the G77-containing clone demonstrated a 3.5-fold greater affinity for b-endorphin than the receptor derived from the C77-containing clone. An assay developed to assess the incidence of the C77G SNP in a behaviorally and physiologically characterized cohort of rhesus monkeys (n ¼ 32) indicated that 44% were homozygous for C77-containing alleles, 50% were heterozygous and 6% were homozygous for G77-containing alleles. The presence of G77-containing alleles was associated with significantly lower basal and ACTH-stimulated plasma cortisol levels (Po0.03-0.05 and Po0.02, respectively) and a significantly higher aggressive threat score (Po0.05) in vivo. In a cohort of 20 monkeys, a trend towards an inverse correlation between aggressive threat and plasma cortisol levels was observed. The findings suggest that mu-opioid receptor haplotypes in monkeys can contribute to individual variability in stress response and related aggression. The data support the use of nonhuman primates to investigate mu-opioid receptor genotype/phenotype relations of relevance to humans. Molecular Psychiatry (2004) 9, 99-108. doi:10.1038/ sj.mp.4001378The human mu-opioid receptor gene contains numerous single nucleotide polymorphisms (SNPs), 1 which may affect mu-opioid receptor structure and/or function. The A118G SNP in the human mu-opioid receptor gene alters the structure of the N-terminal extracellular arm of the encoded receptor protein, which results in enhanced b-endorphin affinity for the receptor, and has been implicated in modulating hypothalamic-pituitary-adrenal (HPA) axis activation . 2,3 Based on our previous studies demonstrating robust genetic similarities between nonhuman primate and human transporters and receptors, 4-7 we explored whether genetic variations of the mu-opioid receptor gene, analogous to humans, exist in rhesus monkey. Cloning of the rhesus monkey mu-opioid receptor coding region revealed a B98% homology to the human coding region. A C77G SNP was discovered that altered an amino acid in the same region (N-terminal arm) as the A118G SNP in the human muopioid receptor. The G77-containing alleles were ...