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Results: 1 to 3 of 3

Publication Record


A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2.
Zhang X, Garbett K, Veeraraghavalu K, Wilburn B, Gilmore R, Mirnics K, Sisodia SS
(2012) J Neurosci 32: 8633-48
MeSH Terms: Animals, Autophagy, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Blastocyst, Blotting, Western, Cathepsin D, Cell Line, Tumor, Cells, Cultured, DNA Primers, Gene Expression, Humans, Hydrogen-Ion Concentration, Lysosomes, Mice, Mice, Knockout, Neurons, Polymerase Chain Reaction, Presenilin-1, Presenilin-2, Presenilins, RNA, RNA, Small Interfering, Vacuolar Proton-Translocating ATPases
Show Abstract · Added May 19, 2014
Presenilins 1 and 2 (PS1 and PS2) are the catalytic subunits of the γ-secretase complex, and genes encoding mutant PS1 and PS2 variants cause familial forms of Alzheimer's disease. Lee et al. (2010) recently reported that loss of PS1 activity lead to impairments in autophagosomal function as a consequence of lysosomal alkalinization, caused by failed maturation of the proton translocating V0a1 subunit of the vacuolar (H+)-ATPase and targeting to the lysosome. We have reexamined these issues in mammalian cells and in brains of mice lacking PS (PScdko) and have been unable to find evidence that the turnover of autophagic substrates, vesicle pH, V0a1 maturation, or lysosome function is altered compared with wild-type counterparts. Collectively, our studies fail to document a role for presenilins in regulating cellular autophagosomal function. On the other hand, our transcriptome studies of PScdko mouse brains reveal, for the first time, a role for PS in regulating lysosomal biogenesis.
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23 MeSH Terms
Diminished taxol/GTP-stimulated tubulin polymerization in diseased region of brain from patients with late-onset or inherited Alzheimer's disease or frontotemporal dementia with parkinsonism linked to chromosome-17 but not individuals with mild cognitive impairment.
Boutté AM, Neely MD, Bird TD, Montine KS, Montine TJ
(2005) J Alzheimers Dis 8: 1-6
MeSH Terms: Aged, Aged, 80 and over, Alzheimer Disease, Brain, Chromosomes, Human, Pair 17, Cognition Disorders, DNA Mutational Analysis, Dementia, Female, Genetic Linkage, Humans, Male, Membrane Proteins, Microtubule-Associated Proteins, Microtubules, Paclitaxel, Parkinsonian Disorders, Presenilin-2, Tubulin, Tubulin Modulators, tau Proteins
Show Abstract · Added September 13, 2014
Neuronal microtubules are morphologically abnormal in diseased regions of brain from patients with late-onset Alzheimer's disease (LOAD). Here we tested the hypothesis that tubulin derived from gray matter of patients with multiple forms of dementia was functionally impaired. Following taxol/GTP stimulation of tubulin polymerization of gray matter extracts we observed reduced capacity of tubulin to polymerize in LOAD, but not individuals with mild cognitive impairment (MCI), compared to controls. Moreover, we observed similarly reduced taxol/GTP-stimulated tubulin polymerization from gray matter obtained from patients with AD caused by PSEN2 N141I mutation or frontotemporal dementia with parkinsonism linked to chromosome-17 caused (FTDP-17) by TAU V337M or P301L mutation. Our results show that modification of tubulin function may contribute to intermediate or late stages in the pathogenesis of sporadic and inherited AD as well as FTDP-17.
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21 MeSH Terms
Analysis of Notch function in presomitic mesoderm suggests a gamma-secretase-independent role for presenilins in somite differentiation.
Huppert SS, Ilagan MX, De Strooper B, Kopan R
(2005) Dev Cell 8: 677-88
MeSH Terms: Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Body Patterning, Cell Differentiation, Endopeptidases, In Situ Hybridization, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Microscopy, Electron, Scanning, Phenotype, Presenilin-1, Presenilin-2, Receptor, Notch1, Receptor, Notch2, Receptors, Cell Surface, Somites, Transcription Factors
Show Abstract · Added January 11, 2011
The role of Notch signaling in general and presenilin in particular was analyzed during mouse somitogenesis. We visualize cyclical production of activated Notch (NICD) and establish that somitogenesis requires less NICD than any other tissue in early mouse embryos. Indeed, formation of cervical somites proceeds in Notch1; Notch2-deficient embryos. This is in contrast to mice lacking all presenilin alleles, which have no somites. Since Nicastrin-, Pen-2-, and APH-1a-deficient embryos have anterior somites without gamma-secretase, presenilin may have a gamma-secretase-independent role in somitogenesis. Embryos triple homozygous for both presenilin null alleles and a Notch allele that is a poor substrate for presenilin (N1(V-->G)) experience fortuitous cleavage of N1(V-->G) by another protease. This restores NICD, anterior segmentation, and bilateral symmetry but does not rescue rostral/caudal identities. These data clarify multiple roles for Notch signaling during segmentation and suggest that the earliest stages of somitogenesis are regulated by both Notch-dependent and Notch-independent functions of presenilin.
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21 MeSH Terms