Raymond J. Kelleher

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Mutations in presenilins are the major cause of familial Alzheimer's disease, but the pathogenic mechanism by which presenilin mutations cause memory loss and neurodegeneration remains unclear. Here we demonstrate that conditional double knockout mice lacking both presenilins in the postnatal forebrain exhibit impairments in hippocampal memory and synaptic(More)
Enduring forms of synaptic plasticity and memory require new protein synthesis, but little is known about the underlying regulatory mechanisms. Here, we investigate the role of MAPK signaling in these processes. Conditional expression of a dominant-negative form of MEK1 in the postnatal murine forebrain inhibited ERK activation and caused selective deficits(More)
Long-term memory and its putative synaptic correlates the late phases of both long-term potentiation and long-term depression require enhanced protein synthesis. On the basis of recent data on translation-dependent synaptic plasticity and on the supralinear effect of activation of nearby synapses on action potential generation, we propose a model for the(More)
Memory and synaptic plasticity exhibit distinct temporal phases, with long-lasting forms distinguished by their dependence on macromolecular synthesis. Prevailing models for the molecular mechanisms underlying long-lasting synaptic plasticity have largely focused on transcriptional regulation. However, a growing body of evidence now supports a crucial role(More)
Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of beta-amyloid (Abeta) peptides, particularly Abeta42, is the central event triggering neurodegeneration. Emerging evidence,(More)
Autism is a complex genetic disorder, but single-gene disorders with a high prevalence of autism offer insight into its pathogenesis. Recent evidence suggests that some molecular defects in autism may interfere with the mechanisms of synaptic protein synthesis. We propose that aberrant synaptic protein synthesis may represent one possible pathway leading to(More)
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent lines of germ-line deletion mice. The dopaminergic(More)
The Tsx gene resides at the X-inactivation center and is thought to encode a protein expressed in testis, but its function has remained mysterious. Given its proximity to noncoding genes that regulate X-inactivation, here we characterize Tsx and determine its function in mice. We find that Tsx is actually noncoding and the long transcript is expressed(More)
Presenilins play essential roles in memory formation, synaptic function, and neuronal survival. Mutations in the Presenilin-1 (PSEN1) gene are the major cause of familial Alzheimer's disease (FAD). How PSEN1 mutations cause FAD is unclear, and pathogenic mechanisms based on gain or loss of function have been proposed. Here, we generated Psen1 knockin (KI)(More)
Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110; and Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Program(More)