Faculty Opinions recommendation of Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway.

2004 ◽  
Author(s):  
Sharon Tooze
Keyword(s):  
Hippocampal Neurons ◽  
Presenilin 1 ◽  
Degradative Pathway

scholarly journals Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway

2004 ◽  
Vol 166 (7) ◽  
pp. 1041-1054 ◽  
Author(s):  
Cary Esselens ◽  
Viola Oorschot ◽  
Veerle Baert ◽  
Tim Raemaekers ◽  
Kurt Spittaels ◽  
...  
Keyword(s):  
Half Life ◽  
Cathepsin D ◽  
Hippocampal Neurons ◽  
Transmembrane Domain ◽  
Presenilin 1 ◽  
Wild Type ◽  
Degradative Pathway ◽  
Autophagic Vacuoles ◽  
Secretase Activity ◽  
Lysosomal Proteins

Presenilin 1 (PS1) interacts with telencephalin (TLN) and the amyloid precursor protein via their transmembrane domain (Annaert, W.G., C. Esselens, V. Baert, C. Boeve, G. Snellings, P. Cupers, K. Craessaerts, and B. De Strooper. 2001. Neuron. 32:579–589). Here, we demonstrate that TLN is not a substrate for γ-secretase cleavage, but displays a prolonged half-life in PS1−/− hippocampal neurons. TLN accumulates in intracellular structures bearing characteristics of autophagic vacuoles including the presence of Apg12p and LC3. Importantly, the TLN accumulations are suppressed by adenoviral expression of wild-type, FAD-linked and D257A mutant PS1, indicating that this phenotype is independent from γ-secretase activity. Cathepsin D deficiency also results in the localization of TLN to autophagic vacuoles. TLN mediates the uptake of microbeads concomitant with actin and PIP2 recruitment, indicating a phagocytic origin of TLN accumulations. Absence of endosomal/lysosomal proteins suggests that the TLN-positive vacuoles fail to fuse with endosomes/lysosomes, preventing their acidification and further degradation. Collectively, PS1 deficiency affects in a γ-secretase–independent fashion the turnover of TLN through autophagic vacuoles, most likely by an impaired capability to fuse with lysosomes.

scholarly journals Presenilin 1 Controls γ-Secretase Processing of Amyloid Precursor Protein in Pre-Golgi Compartments of Hippocampal Neurons

1999 ◽  
Vol 147 (2) ◽  
pp. 277-294 ◽  
Author(s):  
Wim G. Annaert ◽  
Lyne Levesque ◽  
Kathleen Craessaerts ◽  
Inge Dierinck ◽  
Greet Snellings ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Amyloid Precursor Protein ◽  
Hippocampal Neurons ◽  
Subcellular Fractionation ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Carboxy Terminal ◽  
Endocytic Pathways

Mutations of presenilin 1 (PS1) causing Alzheimer's disease selectively increase the secretion of the amyloidogenic βA4(1-42), whereas knocking out the gene results in decreased production of both βA4(1-40) and (1-42) amyloid peptides (De Strooper et al. 1998). Therefore, PS1 function is closely linked to the γ-secretase processing of the amyloid precursor protein (APP). Given the ongoing controversy on the subcellular localization of PS1, it remains unclear at what level of the secretory and endocytic pathways PS1 exerts its activity on APP and on the APP carboxy-terminal fragments that are the direct substrates for γ-secretase. Therefore, we have reinvestigated the subcellular localization of endogenously expressed PS1 in neurons in vitro and in vivo using confocal microscopy and fine-tuned subcellular fractionation. We show that uncleaved PS1 holoprotein is recovered in the nuclear envelope fraction, whereas the cleaved PS fragments are found mainly in post-ER membranes including the intermediate compartment (IC). PS1 is concentrated in discrete sec23p- and p58/ERGIC-53–positive patches, suggesting its localization in subdomains involved in ER export. PS1 is not found to significant amounts beyond the cis-Golgi. Surprisingly, we found that APP carboxy-terminal fragments also coenrich in the pre-Golgi membrane fractions, consistent with the idea that these fragments are the real substrates for γ-secretase. Functional evidence that PS1 exerts its effects on γ-secretase processing of APP in the ER/IC was obtained using a series of APP trafficking mutants. These mutants were investigated in hippocampal neurons derived from transgenic mice expressing PS1wt or PS1 containing clinical mutations (PS1M146L and PS1L286V) at physiologically relevant levels. We demonstrate that the APP-London and PS1 mutations have additive effects on the increased secretion of βA4(1-42) relative to βA4(1-40), indicating that both mutations operate independently. Overall, our data clearly establish that PS1 controls γ42-secretase activity in pre-Golgi compartments. We discuss models that reconcile this conclusion with the effects of PS1 deficiency on the generation of βA4(1-40) peptide in the late biosynthetic and endocytic pathways.

P4-270 A γ-secretase independent role for presenilin 1 in telencephalin turnover in hippocampal neurons

2004 ◽  
Vol 25 ◽  
pp. S552
Author(s):  
Cary Esselens ◽  
Viola Oorschot ◽  
Veerle Baert ◽  
Tim Raemaekers ◽  
Bart De Strooper ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Presenilin 1

scholarly journals Mutant Presenilin 1 Alters Synaptic Transmission in Cultured Hippocampal Neurons

2006 ◽  
Vol 282 (2) ◽  
pp. 1119-1127 ◽  
Author(s):  
Christina Priller ◽  
Ilse Dewachter ◽  
Neville Vassallo ◽  
Sandra Paluch ◽  
Claudia Pace ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Hippocampal Neurons ◽  
Presenilin 1 ◽  
Cultured Hippocampal Neurons

Mice expressing human mutant presenilin-1 exhibit decreased activation of NF-κB p50 in hippocampal neurons after injury

2003 ◽  
Vol 110 (1) ◽  
pp. 152-157 ◽  
Author(s):  
C.A Kassed ◽  
T.L Butler ◽  
M.T Navidomskis ◽  
M.N Gordon ◽  
D Morgan ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Presenilin 1

scholarly journals Increased Vulnerability of Hippocampal Neurons from Presenilin-1 Mutant Knock-In Mice to Amyloid β-Peptide Tox

2008 ◽  
Vol 72 (3) ◽  
pp. 1019-1029 ◽  
Author(s):  
Qing Guo ◽  
Lois Sebastian ◽  
Bryce L. Sopher ◽  
Miles W. Miller ◽  
Carol B. Ware ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Amyloid Β ◽  
Presenilin 1 ◽  
Amyloid Β Peptide

Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice

10.1038/4789 ◽  
1999 ◽  
Vol 5 (1) ◽  
pp. 101-106 ◽  
Author(s):  
Qing Guo ◽  
Weiming Fu ◽  
Bryce L. Sopher ◽  
Miles W. Miller ◽  
Carol B. Ware ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Presenilin 1

scholarly journals Presenilin 1 Regulates [Ca2+]i and Mitochondria/ER Interaction in Cultured Rat Hippocampal Neurons

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Eduard Korkotian ◽  
Anna Meshcheriakova ◽  
Menahem Segal
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Survival Rate ◽  
Hippocampal Neurons ◽  
Presenilin 1 ◽  
Abrupt Increase ◽  
Lower Survival Rate ◽  
Neuronal Functions ◽  
Mushroom Spines

Mutations in the presenilin 1 (PS1) gene are a major trigger of familial Alzheimer’s disease (AD), yet the mechanisms affected by mutated PS1 causing cognitive decline are not yet elucidated. In the present study, we compared rat hippocampal neurons in culture, transfected with PS1 or with mutant (M146V) PS1 (mPS1) plasmids in several neuronal functions. Initially, we confirmed earlier observations that mPS1-expressing neurons are endowed with fewer mature “mushroom” spines and more filopodial immature protrusions. The correlation between calcium changes in the cytosol, mitochondria, and endoplasmic reticulum (ER) is mitigated in the mPS1 neurons, tested by the response to an abrupt increase in ambient [Ca2+]o; cytosolic [Ca2+]i is higher in the mPS1 neurons but mitochondrial [Ca2+] is lower than in control neurons. Strikingly, mPS1-transfected neurons express higher excitability and eventual lower survival rate when exposed to the oxidative stressor, paraquat. These results highlight an impaired calcium regulation in mPS1 neurons, resulting in a reduced ability to handle oxidative stress, which may lead to cell death and AD.

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