document
1
Empty store Full store + Plasma membrane InsP 3 R InsP 3 R Ins(1,4,5)P 3 Endoplasmic reticulum Ca 2+ Ca 2+ The recent discovery of nicastrin as a partner for presenilin highlighted once again the putative proteolytic role of this protein and its identity as γ- secretase. However, there seems to be more to the role of the presenilins than just cleaving the amyloid precursor and other membrane proteins. For example, presenilins can affect calcium homeostasis, presumably by potentiating the inositol-1,4,5-trisphosphate (Ins(1,4,5)P 3 )-mediated Ca 2+ release from intracellular stores.Yoo et al. have tried to gain further insight into the actions of the presenilins on calcium dynamics by focusing on a process tightly linked to Ca 2+ release from intracellular pools — capacitive calcium entry (CCE). When intracellular stores release their calcium contents, CCE takes place through plasma membrane channels presumably activated by the Ins(1,4,5)P 3 receptor itself . This extra intracellular calcium is then used to replenish the stores.Yoo et al. found that CCE (and no other routes of calcium influx) is modulated by the presenilins. In the absence of presenilin-1, or in the presence of an inactive form of this protein, CCE was enhanced in cultured neurons. Conversely, presenilin mutants that increase the production of the amyloidogenic peptide Aβ42, attenuated CCE. Furthermore, the putative CCE-associated current I CRAC was also reduced in the presence of the ‘gain-of-function’ mutant presenilins. An intriguing finding in this study was the fact that blocking CCE by pharmacological means increased the production of Aβ42, an effect dependent on the presence of a functional presenilin-1. However, increasing Aβ42 by other manipulations did not lead to a reciprocal change on CCE amplitude. These observations indicate that the modulation of CCE by the presenilins may be an event upstream of γ-secretase activity, pointing to this route of calcium influx as a possible target for therapeutic approaches against Alzheimer’s disease. It will be important to establish the actual mechanism whereby presenilins affect CCE. Do they modulate calcium entry by proteolysis of a modulatory element? If this were the case, it would expand the list of molecules susceptible to the action of the presenilins and it would point to a more general role for these molecules in the metabolism of membrane proteins. Juan Carlos López References and links ORIGINAL RESEARCH PAPER Yoo, A. S. et al. Presenilin-mediated modulation of capacitive calcium entry. Neuron 27, 561–572 (2000) FURTHER READING Vassar, R. & Citron, M. Aβ-generating enzymes: recent advances in β- and γ-secretase research. Neuron 27, 419–422 (2000) | Yu, G. et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature 407, 48–54 (2000) | Berridge, M. J. et al. The versatility and universality of calcium signalling. Nature Rev. Mol. Cell Biol. 1, 11–21 (2000) WEB SITE The Alzheimer’s web 86 | NOVEMEBER 2000 | VOLUME 1 www.nature.com/reviews/neuro HIGHLIGHTS IN BRIEF Multi-purpose presenilins NEURODEGENERATION Functional connections are established in the deafferented rat spinal cord by peripherally transplanted human embryonic sensory neurons. Levinsson, A. et al. Eur. J. Neurosci. 12, 3589–3595 (2000). Embryonic human sensory neurons were grafted in place of adult rat dorsal root ganglia. The grafted cells extended processes that invaded the dorsal horn, forming branches and then synaptic contacts with host neurons. In addition, the cells were capable of evoking polysynaptic reflexes in the ventral roots, revealing an significant degree of functional integration. This highlights the potential of human embryonic sensory neurons for tissue repair. Oligomeric tubulin in large transporting complex is transported via kinesin in squid giant axons. Terada, S. et al. Cell 103, 141–155 (2000). The transport of fluorescent tubulin was measured in real time in the squid giant axon. Contrary to previous ideas, tubulin transport was found to depend on kinesin, a microtubule-based motor, and not on actin-based motors. Furthermore, by using fluorescence-correlation spectroscopy, the authors obtained an estimate of the number of fluorescent molecules transported in a complex and observed that tubulin is not transported as a stable polymer, as previously thought, but as a smaller oligomer. Synaptic mechanisms and network dynamics underlying spatial working memory in a cortical network model. Compte, A. et al. Cerebral cortex. 10, 910–923 (2000). A network model accounting for the persistent activity observed in the prefrontal cortex during spatial working memory tasks. The current model shows bistability between a resting state with low frequency, spontaneous firing, and a spatially-structured state with higher-frequency firing. This is achieved by a combination of an overall recurrent inhibitory influence and NMDA receptor- mediated recurrent synaptic excitation, features not present in previous pattern formation models. Cell interactions within nascent neural crest cell populations transiently promote death of neurogenic progenitors. Maynard, T. M. et al. Development 127, 4561–4572 (2000). During neural crest cell migration, early, but not late, migratory populations have neurogenic potential. This study shows that neurogenic precursors that fail to disperse early die as a result of cell–cell interactions. Caspase inhibitors prevent this death. Cells that migrated successfully during the early period were no longer susceptible to the influence of cell contact. This was partly mediated by Notch–Delta interactions, and may be a mechanism for assuring that late migratory populations lack neurogenic potential. DEVELOPMENT WORKING MEMORY CELL BIOLOGY OF THE NEURON BRAIN REPAIR Figure adapted from Berridge, M. J. et al. Nature Rev. Mol. Cell Biol. 1, 11–21 (2000). © 2000 Macmillan Magazines Ltd
Transcript of document
Emptystore
Fullstore
+
Plasmamembrane
InsP3R
InsP3R
Ins(1,4,5)P3
Endoplasmicreticulum
Ca2+
Ca2+
The recent discovery of nicastrin as a partner for presenilin highlightedonce again the putative proteolytic role of this protein and its identity as γ-secretase. However, there seems to be more to the role of the presenilinsthan just cleaving the amyloid precursor and other membrane proteins.For example, presenilins can affect calcium homeostasis, presumably bypotentiating the inositol-1,4,5-trisphosphate (Ins(1,4,5)P
3)-mediated Ca2+
release from intracellular stores. Yoo et al. have tried to gain further insightinto the actions of the presenilins on calcium dynamics by focusing on aprocess tightly linked to Ca2+ release from intracellular pools — capacitivecalcium entry (CCE).
When intracellular stores release their calcium contents, CCE takesplace through plasma membrane channels presumably activated by theIns(1,4,5)P
3receptor itself . This extra intracellular calcium is then used to
replenish the stores. Yoo et al. found that CCE (and no other routes ofcalcium influx) is modulated by the presenilins. In the absence ofpresenilin-1, or in the presence of an inactive form of this protein, CCE wasenhanced in cultured neurons. Conversely, presenilin mutants thatincrease the production of the amyloidogenic peptide Aβ42, attenuatedCCE. Furthermore, the putative CCE-associated current I
CRACwas also
reduced in the presence of the ‘gain-of-function’ mutant presenilins.An intriguing finding in this study was the fact that blocking CCE by
pharmacological means increased the production of Aβ42, an effectdependent on the presence of a functional presenilin-1. However, increasingAβ42 by other manipulations did not lead to a reciprocal change on CCEamplitude. These observations indicate that the modulation of CCE by thepresenilins may be an event upstream of γ-secretase activity, pointing tothis route of calcium influx as a possible target for therapeutic approachesagainst Alzheimer’s disease.
It will be important to establish the actual mechanism wherebypresenilins affect CCE. Do they modulate calcium entry by proteolysis of amodulatory element? If this were the case, it would expand the list ofmolecules susceptible to the action of the presenilins and it would point toa more general role for these molecules in the metabolism of membraneproteins.
Juan Carlos López
References and linksORIGINAL RESEARCH PAPER Yoo, A. S. et al. Presenilin-mediated modulation of capacitive calciumentry. Neuron 27, 561–572 (2000)FURTHER READING Vassar, R. & Citron, M. Aβ-generating enzymes: recent advances in β- and γ-secretase research. Neuron 27, 419–422 (2000) | Yu, G. et al. Nicastrin modulates presenilin-mediatednotch/glp-1 signal transduction and βAPP processing. Nature 407, 48–54 (2000) | Berridge, M. J. et al.The versatility and universality of calcium signalling. Nature Rev. Mol. Cell Biol. 1, 11–21 (2000)WEB SITE The Alzheimer’s web
86 | NOVEMEBER 2000 | VOLUME 1 www.nature.com/reviews/neuro
H I G H L I G H T S
IN BRIEF
Multi-purpose presenilins
N E U R O D E G E N E R AT I O N
Functional connections are established in thedeafferented rat spinal cord by peripherallytransplanted human embryonic sensory neurons. Levinsson, A. et al. Eur. J. Neurosci. 12, 3589–3595 (2000).
Embryonic human sensory neurons were grafted in place of adultrat dorsal root ganglia. The grafted cells extended processes thatinvaded the dorsal horn, forming branches and then synapticcontacts with host neurons. In addition, the cells were capable ofevoking polysynaptic reflexes in the ventral roots, revealing ansignificant degree of functional integration. This highlights thepotential of human embryonic sensory neurons for tissue repair.
Oligomeric tubulin in large transporting complex istransported via kinesin in squid giant axons. Terada, S. et al. Cell 103, 141–155 (2000).
The transport of fluorescent tubulin was measured in real time inthe squid giant axon. Contrary to previous ideas, tubulintransport was found to depend on kinesin, a microtubule-basedmotor, and not on actin-based motors. Furthermore, by usingfluorescence-correlation spectroscopy, the authors obtained anestimate of the number of fluorescent molecules transported in acomplex and observed that tubulin is not transported as a stablepolymer, as previously thought, but as a smaller oligomer.
Synaptic mechanisms and network dynamics underlyingspatial working memory in a cortical network model.Compte, A. et al. Cerebral cortex. 10, 910–923 (2000).
A network model accounting for the persistent activity observedin the prefrontal cortex during spatial working memory tasks. Thecurrent model shows bistability between a resting state with lowfrequency, spontaneous firing, and a spatially-structured statewith higher-frequency firing. This is achieved by a combination ofan overall recurrent inhibitory influence and NMDA receptor-mediated recurrent synaptic excitation, features not present inprevious pattern formation models.
Cell interactions within nascent neural crest cellpopulations transiently promote death of neurogenicprogenitors.Maynard, T. M. et al. Development 127, 4561–4572 (2000).
During neural crest cell migration, early, but not late, migratorypopulations have neurogenic potential. This study shows thatneurogenic precursors that fail to disperse early die as a result ofcell–cell interactions. Caspase inhibitors prevent this death. Cellsthat migrated successfully during the early period were no longersusceptible to the influence of cell contact. This was partly mediatedby Notch–Delta interactions, and may be a mechanism for assuringthat late migratory populations lack neurogenic potential.
D E V E LO P M E N T
W O R K I N G M E M O R Y
C E L L B I O LO G Y O F T H E N E U R O N
B R A I N R E PA I R
Figure adapted from Berridge, M. J. et al. Nature Rev. Mol. Cell Biol. 1, 11–21 (2000).
© 2000 Macmillan Magazines Ltd
