Donald C. Lo
Duke University
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Featured researches published by Donald C. Lo.
Neuron | 1997
A. Kimberley McAllister; Lawrence C Katz; Donald C. Lo
Neurons within each layer of cerebral cortex express multiple members of the neurotrophin family and their corresponding receptors. This multiplicity could provide functional redundancy; alternatively, different neurotrophins may direct distinct aspects of cortical neuronal growth and differentiation. By neutralizing endogenous neurotrophins in organotypic slices of developing cortex with Trk receptor bodies (Trk-IgGs), we found that BDNF and NT-3 oppose one another in regulating the dendritic growth of pyramidal neurons. In layer 4, both endogenous and exogenous NT-3 inhibited the dendritic growth stimulated by BDNF. In contrast, in layer 6 both endogenous and exogenous BDNF inhibited dendritic growth stimulated by NT-3. These antagonistic actions of endogenous BDNF and NT-3 provide a mechanism by which dendritic growth and retraction can be dynamically regulated during cortical development, and suggest that the multiple neurotrophins expressed in developing cortex represent distinct components of an extracellular signaling system for regulating dendritic growth.
Neuron | 1996
A. Kimberley McAllister; Lawrence C Katz; Donald C. Lo
Neurotrophins have been proposed to mediate several forms of activity-dependent competition in the central nervous system. A key element of such hypotheses is that neurotrophins act preferentially on active neurons; however, little direct evidence supports this postulate. We therefore examined, in ferret cortical brain slices, the interactions between activity and neurotrophins in regulating dendritic growth of layer 4 pyramidal neurons. Inhibition of spontaneous electrical activity, synaptic transmission, or L-type calcium channels each prevented the otherwise dramatic increase in dendritic arborizations elicited by brain-derived neurotrophic factor. In developing cortex, this requirement for conjoint neurotrophin signaling and activity provides a mechanism for selectively enhancing the growth and connectivity of active neurons.
Neuron | 1995
Donald C. Lo
Models of activity-dependent synaptic plasticity, whether in the context of development or of learning and memory, have long postulated the existence of extracellular signal-ing molecules that enhance and stabilize active synapses. In recent years, neurotrophic factors have emerged as attractive candidates for such signaling molecules. The work of several laboratories has shown that neurotrophins fulfill the two major criteria for any such mediators of syn-aptic plasticity: their production is regulated by neuronal activity, and neurotrophic factors, in turn, have potent effects on the signaling properties of target neurons. Neuro-trophic factors represent a new and exciting class of molecules for a signaling role in synaptic plasticity because of their strong regulation of gene expression and neuronal morphology; neurotrophic factors could consequently regulate neuronal excitability and synaptic function over a much longer time scale than conventional neuromodulators. The neurotrophic factors that have been most studied in this regard are the neurotrophins, which are much better known for their promotion of neuronal survival and differentiation. Nerve growth factor (NGF) remains the arche-typical neurotrophin; in addition, the neurotrophin family now includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, and NT-6 (reviewed in Lind-say et al., 1994; GOtz et al., 1994). Responsiveness to particular neurotrophins is mediated through receptors specific for each factor. These receptors, members of the trk family of protooncogenes, are receptor tyrosine ki-nases related to other peptide factor receptors such as insulin and epidermal growth factor (EGF) receptors. Although cross-activation can occur, in neurons TrkA is primarily a receptor for NGF, TrkB a receptor for BDNF and NT-4/5, and TrkC a receptor for NT-3. Regulation of neurotrophin mRNA levels by activity was first discovered in the hippocampus, where high basal levels of neurotrophins are expressed. NGF and BDNF mRNA levels, but not those for NT-3, are rapidly and strongly regulated by epileptiform activity in the hippocam-pus; even a single epileptiform afterdischarge is sufficient to increase levels of NGF and BDNF mRNA substantially (e.g., Ernfors et al., 1991; Isackson et al., 1991). Changes in BDNF mRNA levels are particularly dramatic, increasing by over 6-fold in dentate granule cells within 30 min after stimulation of seizure activity (Ernfors et al., 1991). These increases in NGF and BDNF mRNAs are transient, returning to control levels after 24 hr (Isackson et al., 1991 ; Ernfors et al., 1991). Importantly, conditions inducing long-term potentiation (LTP) in the hippocampus have also been shown to increase BDNF and NT-3 …
Nature Neuroscience | 2000
Talene A. Yacoubian; Donald C. Lo
Neurotrophin regulation of neuronal morphology is complex and may involve differential action of alternative Trk receptor isoforms. We transfected ferret visual cortical slices with full-length and truncated TrkB receptors to examine their roles in regulating cortical dendrite development. These TrkB isoforms had differential effects on dendritic arborization: whereas full-length TrkB increased proximal dendritic branching, truncated TrkB promoted net elongation of distal dendrites. The morphological effects of each receptor isoform were distinct, yet their actions inhibited one another. Actions of the truncated TrkB receptor did not involve unmasking of endogenous TrkC signaling. These results suggest that TrkB receptors do not regulate dendritic growth per se but, rather, the mode of such growth.
Journal of Cell Biology | 2009
Leslie M. Thompson; Charity T. Aiken; Linda S. Kaltenbach; Namita Agrawal; Ali Khoshnan; Marta Martinez-Vincente; Montserrat Arrasate; Jacqueline Gire O'Rourke; Hasan Khashwji; Tamas Lukacsovich; Ya Zhen Zhu; Alice L. Lau; Ashish C. Massey; Michael R. Hayden; Scott O. Zeitlin; Steven Finkbeiner; Kim N. Green; Frank M. LaFerla; Gillian P. Bates; Lan Huang; Paul H. Patterson; Donald C. Lo; Ana Maria Cuervo; J. Lawrence Marsh; Joan S. Steffan
The protein mutated in Huntingtons disease is phosphorylated by the inflammatory kinase IKK, which promotes other post-translational modifications, and protein degradation.
Neuron | 1994
Donald C. Lo; A. Kimberley McAllister; Lawrence C Katz
Difficulties in neuronal transfection continue to restrict the applicability of molecular approaches to neurobiology. Conventional transfection techniques have been of limited effectiveness, particularly in intact neural tissues. Viral vectors effectively transfect neurons both in vitro and in vivo but are labor intensive to construct, difficult to control, and often compromise cell viability. We describe here an alternative strategy using particle-mediated gene transfer for the transfection of neurons and glia in intact brain slices. This approach is efficient, reliable, and does not require advanced molecular biological facilities for its application.
Nature Chemical Biology | 2010
Benjamin Hoffstrom; Anna Kaplan; Reka R. Letso; Ralf S. Schmid; Gregory J. Turmel; Donald C. Lo; Brent R. Stockwell
A hallmark of many neurodegenerative diseases is accumulation of misfolded proteins within neurons, leading to cellular dysfunction and cell death. Although several mechanisms have been proposed to link protein misfolding to cellular toxicity, the connection remains enigmatic. Here, we report a cell death pathway involving protein disulfide isomerase (PDI), a protein chaperone that catalyzes isomerization, reduction, and oxidation of disulfides. Through a small-molecule-screening approach, we discovered five structurally distinct compounds that prevent apoptosis induced by mutant huntingtin protein. Using modified Huisgen cycloaddition chemistry, we then identified PDI as the molecular target of these small molecules. Expression of polyglutamine-expanded huntingtin exon 1 in PC12 cells caused PDI to accumulate at mitochondrial-associated-ER-membranes and trigger apoptotic cell death, via mitochondrial outer membrane permeabilization. Inhibiting PDI in rat brain cells suppressed the toxicity of mutant huntingtin exon1 and Aβ peptides processed from the amyloid precursor protein. This pro-apoptotic function of PDI provides a new mechanism linking protein misfolding and apoptotic cell death.
Journal of the American Chemical Society | 2014
Rachid Skouta; Scott J. Dixon; Jianlin Wang; Denise E. Dunn; Marina Orman; Kenichi Shimada; Paul A. Rosenberg; Donald C. Lo; Joel M. Weinberg; Andreas Linkermann; Brent R. Stockwell
Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington’s disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes.
Nature Neuroscience | 2006
Isabel Pérez-Otaño; Rafael Luján; Steven J. Tavalin; Markus Plomann; Jan Modregger; Xiao Bo Liu; Edward G. Jones; Stephen F. Heinemann; Donald C. Lo; Michael D. Ehlers
A key step in glutamatergic synapse maturation is the replacement of developmentally expressed N-methyl-D-aspartate receptors (NMDARs) with mature forms that differ in subunit composition, electrophysiological properties and propensity to elicit synaptic plasticity. However, the mechanisms underlying the removal and replacement of synaptic NMDARs are poorly understood. Here we demonstrate that NMDARs containing the developmentally regulated NR3A subunit undergo rapid endocytosis from the dendritic plasma membrane in cultured rat hippocampal neurons. This endocytic removal is regulated by PACSIN1/syndapin1, which directly and selectively binds the carboxy-terminal domain of NR3A through its NPF motifs and assembles a complex of proteins including dynamin and clathrin. Endocytosis of NR3A by PACSIN1 is activity dependent, and disruption of PACSIN1 function causes NR3A accumulation at synaptic sites. Our results reveal a new activity-dependent mechanism involved in the regulation of NMDAR expression at synapses during development, and identify a brain-specific endocytic adaptor that confers spatiotemporal and subunit specificity to NMDAR endocytosis.
Journal of Medicinal Chemistry | 2012
Tania Tahtouh; J.M. Elkins; Panagis Filippakopoulos; Meera Soundararajan; Guillaume Burgy; Emilie Durieu; Claude Cochet; Ralf S. Schmid; Donald C. Lo; Florent Delhommel; Anselm Erich Oberholzer; Laurence H. Pearl; François Carreaux; Jean Pierre Bazureau; Stefan Knapp; Laurent Meijer
DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimers disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimers disease.