Focus Issue: Brain Disease--Signaling on My Mind

Of the myriad disorders to which human flesh is heir, perhaps the most dreaded are those that affect our brains. From the neurodevelopmental disorders that can strike before birth or in childhood, to the neuropsychiatric disorders that most commonly appear in the prime of life, to the neurodegenerative diseases that predominantly occur in old age, brain diseases can disrupt our relationships with others, rob us of our independence, and even, in some cases, destroy our very sense of self. This week's Special Issue of Science and Focus Issue of Science 's STKE feature articles that attempt to illuminate the biological bases of these potentially devastating illnesses and to discuss how elucidation of the pathogenesis of these disorders may point the way toward advances in their therapy and diagnosis. In a Review in Science , Zoghbi discusses the hypothesis that two postnatal neurodevelopmental disorders in which active alert infants become uncommunicative and socially withdrawn, autism and Rett syndrome, are associated with the disruption of synaptic modulation or maintenance. Whereas autism has been associated with various mutations, Rett syndrome has been linked to a mutation in the gene encoding methyl-CpG-binding protein 2 (MeCP2), the loss of whose function, in Xenopus , has been associated with disruption of neuronal differentiation mediated through the Notch-Delta signaling pathway. Reports in Science from Chen et al . and Martinowich et al . point to a new mechanism of action for MeCP2 in which the protein mediates acute changes in neuronal gene expression in response to depolarization. A Review by Golde and Eckman in the STKE Archives describes the role of γ-secretase-mediated proteolysis in Notch signaling, as well as the role of γ-secretase cleavage of amyloid precursor protein in producing an amyloid β peptide (Aβ) implicated in the development of amyloid plaques and the pathogenesis of Alzheimer's disease. The γ-secretase pathway, and the roles of individual members of the γ-secretase complex, such as the presenilins, are further described in a Science Review by Aguzzi and Haass on the role of "rogue proteins" in neurodegenerative disorders, such as the prion diseases and Alzheimer's disease. Mutations in the genes that encode amyloid precursor protein and the presenilins are among those associated with susceptibility to Alzheimer's disease, as discussed by Kennedy et al . in a Science Review on genetic factors that contribute to adult-onset neurodegenerative and neuropsychiatric diseases, including Alzheimer's disease, the fronto-temporal dementias, and schizophrenia. Genomic approaches to drug development for such disorders as depression and schizophrenia are the topic of the Perspective by Levy in the STKE Archive. The microarray analysis described also provides clues into the molecular mechanisms that contribute to these diseases. Manji et al . discuss the possible contribution of abnormalities in the direct and indirect modulation of intracellular signaling pathways to the pathogenesis of neuropsychiatric diseases, including recent evidence implicating the protein phosphatase calcineurin as a schizophrenia susceptibility gene, in an STKE Perspective. Intriguingly, calcineurin may play a role in modulating both signaling through dopaminergic and glutamatergic pathways--the two neurotransmitter systems whose dysfunction has been most strongly implicated in contributing to the acute manifestations of schizophrenia--and signaling through neurotrophic pathways that may contribute to the chronic course of the disease. As the authors discuss, calcineurin-mediated inactivation of dopamine and cyclic adenosine monophosphate (cAMP)-regulated phosphoprotein of 32 kD (DARPP-32) may be key to its regulation of both dopaminergic and glutamatergic signaling. In a Perspective in the STKE Archives, Bastia and Schwarzschild discuss research suggesting a role for DARPP-32 in mediating the sustained psychomotor stimulant effect produced by low doses of caffeine, as well as the possible role of DARPP-32 in caffeine's neuroprotective action on dopaminergic neurons. The loss of dopaminergic neurons underlies the clinical symptoms of Parkinson's disease, the most common neurodegenerative movement disorder. In a Science Review, Dawson and Dawson describe the molecular pathways that may lead to the loss of these neurons, highlighting the role of mitochondrial complex I, α-synuclein, and the ubiquitin-proteasomal system in dopaminergic neuron death. The authors present a model in which deficits in complex I activity lead to an environment of oxidative stress that promotes the aggregation and accumulation of α-synuclein, which leads to dysfunction of the proteasome and thereby cell death. Among the articles in the STKE Archives that focus on the ubiquitin-proteasomal system, a Perspective by Schwartz discusses the role of ubiquitin-mediated degradation in synaptic plasticity. Abnormalities in neurotransmitter signaling systems can also arise from changes in neurotransmitter concentration at the synapse consequent to changes in the numbers or activity of neurotransmitter transporters. In an STKE Perspective, Robinson discusses the association of mutations in several neurotransmitter transporters with different neuropsychiatric disorders, the signaling pathways involved in regulating the activity and the availability of neurotransmitter transporters, and the role of neurotransmitter transporters as targets for clinically important drugs. A mutation in the HD gene that increases the number of glutamines in the encoded huntingtin protein has been implicated in the pathogenesis of the neurodegenerative movement disorder Huntington's disease. In an STKE Perspective, MacDonald discusses the likelihood that huntingtin functions as a scaffolding protein, and its possible role in organizing signaling complexes and thereby facilitating signaling through various intracellular pathways. Two Reviews in Science discuss applications of our knowledge of brain disease to advance its diagnosis and treatment. Aβ production and amyloid plaque formation are accompanied by innate immune responses, which include secretion of proinflammatory cytokines and nitric oxide and activation of microglia, and an increase in the numbers of peripheral Aβ-reactive T cells. Monsonego and Weiner discuss means by which the adaptive immune response can be modulated as an approach to the therapy of Alzheimer's disease and other neurodegenerative disorders. Finally, DeKosky and Marek discuss strategies whereby advances in our understanding of the molecular bases of diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease can be used to detect them early in their course and thereby pave the way to the development of more effective treatments. Featured in This Focus Issue Perspectives Virtual Journal Related Resources at STKE Perspectives Reviews