The angiotensin-converting enzyme gene insertion/deletion polymorphism interacts with fear of falling in relation to stepping speed in community-dwelling older adults.

BACKGROUND: Despite the association of genetic factors with falls, balance, and lower extremity functioning, interaction of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with fear of falling (FOF) in relation to stepping performance has, to the best of our knowledge, not been investigated in older adults. OBJECTIVE: The purpose of this study was to examine the interaction effects of the ACE I/D polymorphism with FOF in relation to stepping performance in older adults. METHODS: Eighty-eight community-dwelling adults 60 years or older participated in a cross-sectional observational study. Participants completed tests of rapid and distance stepping, and self-reported FOF (yes/no). Participants provided saliva for ACE genotyping. General linear models evaluated ACE genotype × FOF interaction effects in relation to stepping performance. The α level was set at 0.05. RESULTS: The ACE I/D polymorphism exhibited significant interaction effects (p for interactions 0.002 ≤ p ≤ .04) with FOF in relation to stepping speed. Relationships between FOF and stepping speed varied among ACE genotypes. The insertion/insertion (II) genotype was significantly associated (p = .01) with slow stepping in individuals with, but not without FOF (p > .05). CONCLUSION: Variation in relationships between FOF and stepping speed among ACE genotypes suggests a role for the ACE I/D polymorphism in modifying relationships between FOF and stepping speed in older adults. The association of the ACE II genotype with slow stepping performance in individuals with, but not without FOF, suggests that older adults with the ACE II genotype and FOF may be at increased risk for poor stepping performance and associated functional declines.

Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism, Lower Extremity Strength, and Physical Performance in Older Adults.

BACKGROUND: Evidence for associations between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and physical performance is conflicting. Furthermore, investigations of relationships between lower extremity strength and physical performance have usually not considered the role of the ACE genotype, and it is unclear whether there are variations in relationships between lower extremity strength and physical performance among ACE genotypes in older adults. OBJECTIVE: The objectives of this study were to investigate associations between the ACE I/D polymorphism and physical performance and to determine whether relationships between lower extremity strength and physical performance vary among ACE genotypes in older adults. DESIGN: This was a cross-sectional observational study. METHODS: Community-dwelling adults (N = 88) who were at least 60 years old completed physical performance and lower extremity strength tests. After DNA was extracted from saliva, ACE I/D polymorphism genotyping was done. The Spearman rank order correlation coefficient was used to examine associations between lower extremity strength and physical performance within ACE genotype subgroups. Analysis of covariance and linear regression were used to examine ACE genotype and ACE genotype × lower extremity strength interaction effects in relation to physical performance. RESULTS: Genotype-specific correlation coefficients exhibited substantial variation among ACE genotype subgroups; however, differences did not attain statistical significance. Statistically significant genotype × lower extremity strength interaction effects in relation to physical performance were detected. LIMITATIONS: The cross-sectional design precludes inferring causal relationships between strength and performance. The small sample size contributed to limited power to detect additional interaction effects and to detect statistically significant differences between correlation coefficients among ACE genotype subgroups. CONCLUSIONS: The ACE I/D polymorphism is, interactively with lower extremity strength, associated with physical performance. Genotype-specific correlation coefficients and ACE genotype × lower extremity strength interaction effects on physical performance are consistent with variations in relationships between lower extremity strength and performance among ACE genotype subgroups.

Altered glial gene expression, density, and architecture in the visual cortex upon retinal degeneration.

Genes encoding the proteins of cytoskeletal intermediate filaments (IF) are tightly regulated, and they are important for establishing neural connections. However, it remains uncertain to what extent neurological disease alters IF gene expression or impacts cells that express IFs. In this study, we determined the onset of visual deficits in a mouse model of progressive retinal degeneration (Pde6b(-) mice; Pde6b(+) mice have normal vision) by observing murine responses to a visual task throughout development, from postnatal day (PND) 21 to adult (N=174 reliable observations). Using Q-PCR, we evaluated whether expression of the genes encoding two Type III IF proteins, glial fibrillary acidic protein (GFAP) and vimentin was altered in the visual cortex before, during, and after the onset of visual deficits. Using immunohistochemical techniques, we investigated the impact of vision loss on the density and morphology of astrocytes that expressed GFAP and vimentin in the visual cortex. We found that Pde6b(-) mice displayed 1) evidence of blindness at PND 49, with visual deficits detected at PND 35, 2) reduced GFAP mRNA expression in the visual cortex between PND 28 and PND 49, and 3) an increased ratio of vimentin:GFAP-labeled astrocytes at PND 49 with reduced GFAP cell body area. Together, these findings demonstrate that retinal degeneration modifies cellular and molecular indices of glial plasticity in a visual system with drastically reduced visual input. The functional consequences of these structural changes remain uncertain.

Effects of age and retinal degeneration on the expression of proprotein convertases in the visual cortex.

Proprotein convertases (PCs) comprise a large family of subtilisin-like, eukaryotic, serine endoproteases that process substrates important in the development, homeostasis, and pathology of the nervous system. Despite important interactions with these substrates, including neurotrophins, PC expression throughout normal postnatal development and disease progression in the brain remains unknown. The primary objective of this study was to determine whether the expression profiles of widely expressed and tissue-specific PCs varied during normal brain development or neurological disorders. We examined the expression of mRNAs for seven PCs in the visual cortex of normal and visually impaired mice at 10 postnatal developmental time points between Week 1 and Week 35. Widely expressed PCs (furin, PACE4, PC5, and PC7) all exhibited a similar expression profile. High mRNA levels were seen at Week 1 with levels generally lower over the next 5-6 weeks. In visually impaired mice, widely expressed PCs again all exhibited a similar expression profile, but it was dramatically different than observed in normal mice. The temporal expression of tissue-specific PCs varied in wild-type mice. Interestingly, this variability was sharply reduced in visually impaired mice. Overall, these data suggest a timetable of altered PC expression that corresponds closely with the formation of functional visual maps in the visual cortex. The implications of these findings are discussed in the context of neurotrophin processing and synaptogenesis in the developing visual cortex.

Intracellular activation of human adamalysin 19/disintegrin and metalloproteinase 19 by furin occurs via one of the two consecutive recognition sites.

Adamalysin 19 (a disintegrin and metalloproteinase 19, ADAM19, or meltrin beta) is a plasma membrane metalloproteinase. Human ADAM19 zymogen contains two potential furin recognition sites (RX(K/R)R), (196)KRPR(200)R and (199)RRMK(203)R, between its pro- and catalytic domains. Protein N-terminal sequencing revealed that the cellular mature forms of hADAM19 started at (204)EDLNSMK, demonstrating that the preferred furin cleavage site was the (200)RMK(203)R downward arrow(204)EDLN. Those mature forms were catalytically active. Both Pittsburgh mutant of alpha(1)-proteinase inhibitor and dec-Arg-Val-Lys-Arg-chloromethyl ketone, two specific furin inhibitors, blocked the activation of hADAM19. Activation of hADAM19 was also blocked by brefeldin A, which inhibits protein trafficking from the endoplasmic reticulum to the Golgi, or, a calcium ionophore known to inhibit the autoactivation of furin. When (202)KR were mutated to AA, the proenzyme was also activated, suggesting that (197)RPRR is an alternative activation site. Furthermore, only pro-forms of hADAM19 were detected in the (199)RR to AA mutant, which abolished both furin recognition sites. Moreover, the zymogens were not converted into their active forms in two furin-deficient mammalian cell lines; co-expression of hADAM19 and furin in these two cell lines restored zymogen activation. Finally, co-localization between furin and hADAM19 was identified in the endoplasmic reticulum-Golgi complex and/or the trans-Golgi network. This report is the first thorough investigation of the intracellular activation of adamalysin 19, demonstrating that furin activated pro-hADAM19 in the secretory pathway via one of the two consecutive furin recognition sites.