Spatial Paradox Research Articles

Innovation And Spatial Externalities

The purpose of this article is to explain the role that spatial externalities play in the current thinking about innovative activity. Geographic space has evolved from being largely neglected in the study of innovative activity to being an integrating unit of observation for analysis. Geographic space provides the platform not just for the creation of new knowledge but also, as a result of the spillover process, for the commercialization of that knowledge. The spatial paradox inherent in innovative activity is that knowledge spills over from the source producing it to the entity actually commercializing that knowledge, which would seemingly suggest that geographic location is irrelevant for accessing new knowledge. The paradox emerges because knowledge spillovers are localized and tend to decay rapidly with transmission across geographic space. Geographic space provides a unit of analysis integrating the various agents—individuals, networks, and enterprises—involved in the innovative process into a coherent unit. This coherent unit clearly extends beyond the boundaries of individual firms yet is defined by geographic space.

Gamma-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation.

Nicastrin and presenilin are two major components of the gamma-secretase complex, which executes the intramembrane proteolysis of type I integral membrane proteins such as the amyloid precursor protein (APP) and Notch. Nicastrin is synthesized in fibroblasts and neurons as an endoglycosidase-H-sensitive glycosylated precursor protein (immature nicastrin) and is then modified by complex glycosylation in the Golgi apparatus and by sialylation in the trans-Golgi network (mature nicastrin). These modifications are not observed with exogenously overexpressed nicastrin. Under normal cell culture conditions, only mature nicastrin is expressed at the cell surface and binds to the presenilin heterodimers. Mature nicastrin has a half-life of more than 24 hours. In the absence of presenilin 1 and 2, nicastrin remains entirely endoglycosidase H sensitive, is retained in the endoplasmic reticulum and is slowly degraded. Single presenilin 1 or presenilin 2 deficiency affects glycosylation of nicastrin to a lesser extent than the combined presenilin deficiencies, suggesting a correlation between either the transport of nicastrin out of the endoplasmic reticulum or the concomitant complex glycosylation of nicastrin, and gamma-secretase activity. However, when complex glycosylation of nicastrin was inhibited using mannosidase I inhibitors, gamma-secretase cleavage of APP or Notch was not inhibited and the immature nicastrin still associates with presenilin and appears at the cell surface. Complex glycosylation of nicastrin is therefore not needed for gamma-secretase activity. Because the trafficking of nicastrin to the Golgi apparatus is dependent on presenilins, our data point to a central role of presenilin in nicastrin maturation/localization, which could help to partially resolve the 'spatial paradox'.

Localization of presenilin-nicastrin complexes and gamma-secretase activity to the trans-Golgi network.

Abundant biochemical and genetic evidence suggests that presenilins are catalytic components of gamma-secretase, the protease responsible for generating the Alzheimer amyloid beta-protein. However, the differential localization of presenilins to early secretory compartments and gamma-secretase substrates to late secretory compartments and the plasma membrane (the "spatial paradox") argues against this view. We investigated this issue by studying the localization of nicastrin, another putative gamma-secretase component, and its association with presenilin-1 into proteolytically active complexes. Glycosidase digests revealed that nicastrin exists in multiple glycoforms and is terminally sialylated, a modification often associated with the trans-Golgi network. Trafficking of nicastrin to the trans-Golgi network was confirmed by density gradient fractionation and immunofluorescence microscopy. In presenilin-deficient cells, however, nicastrin trafficking and maturation were abnormal, as the protein was restricted to early secretory compartments and failed to be sialylated. Mature sialylated nicastrin in trans-Golgi network fractions was complexed quantitatively with N- and C-terminal fragments of presenilin-1, whereas immature nicastrin present in early secretory compartments was not. Additionally, trans-Golgi network fractions contained the gamma-secretase substrate beta-amyloid precursor protein C83 and were enriched in presenilin-dependent gamma-secretase proteolytic activity. The results resolve the apparent spatial paradox by demonstrating that presenilin-nicastrin complexes and presenilin-dependent gamma-secretase activity are co-localized to a late secretory compartment. The findings provide further evidence that presenilin-containing complexes are the gamma-secretase, and indicate that presenilins also regulate gamma-secretase assembly.

Presenilins, γ-Secretase, and the Spatial Paradox

Just when it was looking as though presenilins were, in all likelihood, responsible for γ-secretase activity, new work by Cupers et al. cautions against making such conclusions. Although cleavage of amyloid precursor protein (APP) is decreased in presenilin 1(PS1)-deficient cells, and completely blocked in PS1- and PS2-doubly deficient cells, the authors looked at the subcellular compartments in which the γ-secretase activity, PS, and APP reside, and because their localizations did not completely coincide ("the spatial paradox"), concluded that PS proteins do not have γ-secretase activity. APP-C99-KK, an APP mutant designed to be an excellent substrate for γ-secretase and retained in the endoplasmic reticulum (ER) where PS1 resides, colocalized with PS1 but was not proteolytically cleaved, indicating that PS1 alone did not have γ-secretase activity. APP-C99-KK-expressing cells treated with brefeldin A, which causes the Golgi complex to disassemble and fuse with the ER, led to the generation of Aβ peptide, a marker of γ-secretase activity, suggesting that some unknown protein or proteins that normally reside downstream in the Golgi complex are required for γ-secretase activity, most likely in the presence of PS1. P. Cupers, M. Bentahir, K. Craessaerts, I. Orlans, H. Vanderstichele, P. Saftig, B. De Strooper, W. Annaert, The discrepancy between presenilin subcellular localization and γ-secretase processing of amyloid precursor protein. J. Cell Biol. 154 , 731-740 (2001). [Abstract] [Full Text]

Presenilins, -Secretase, and the Spatial Paradox

Just when it was looking as though presenilins were, in all likelihood, responsible for γ-secretase activity, new work by Cupers et al. cautions against making such conclusions. Although cleavage of amyloid precursor protein (APP) is decreased in presenilin 1(PS1)-deficient cells, and completely blocked in PS1- and PS2-doubly deficient cells, the authors looked at the subcellular compartments in which the γ-secretase activity, PS, and APP reside, and because their localizations did not completely coincide ("the spatial paradox"), concluded that PS proteins do not have γ-secretase activity. APP-C99-KK, an APP mutant designed to be an excellent substrate for γ-secretase and retained in the endoplasmic reticulum (ER) where PS1 resides, colocalized with PS1 but was not proteolytically cleaved, indicating that PS1 alone did not have γ-secretase activity. APP-C99-KK-expressing cells treated with brefeldin A, which causes the Golgi complex to disassemble and fuse with the ER, led to the generation of Aβ peptide, a marker of γ-secretase activity, suggesting that some unknown protein or proteins that normally reside downstream in the Golgi complex are required for γ-secretase activity, most likely in the presence of PS1.P. Cupers, M. Bentahir, K. Craessaerts, I. Orlans, H. Vanderstichele, P. Saftig, B. De Strooper, W. Annaert, The discrepancy between presenilin subcellular localization and γ-secretase processing of amyloid precursor protein. J. Cell Biol. 154, 731-740 (2001). [Abstract] [Full Text]

The Paradox Topos

As William Egginton points out, 1 when Dante and Beatrice step outside the cosmos, they step into another set of concentric spheres. 2 These surround our (supposedly) geocentric cosmos, and yet they center upon God. The image affronts our logic of space. If these concentric spheres encompass us, how can they center upon something somewhere else? The notion seems to turn space inside-out. But Dante's spatial paradox is not in truth a paradox of space. Instead, it is a spiritual paradox, set in terms of space. When Dante and Beatrice step outside the cosmos, they step outside space into an old philosophical topos, a spatial image of God. For that reason, Dante's image is not really akin to the spatial paradoxes of modern astrophysics, although Egginton's comparison of the two does provoke some fascinating comments upon medieval concepts of space. Egginton assesses Dante's paradox in light of medieval debates about space, place, and God. However, he overlooks the most important source for Dante's paradox--the symbolic geometry of Neoplatonic philosophy. 3