Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members

Herms, Jochen; Anliker, Brigitte; Heber, Sabine; Ring, Sabine; Fuhrmann, Martin; Kretzschmar, Hans; Sisodia, Sangram S.; Müller, Ulrike

doi:10.1038/sj.emboj.7600390

Cited by 293 publications

(315 citation statements)

References 51 publications

Supporting

Mentioning

299

Contrasting

Unclassified

Order By: Relevance

“…To get an evident phenotype in mammals, two genes, Fe65 and Fe65L1, should be ablated. These mice show cortical dysplasia (26), also in this case similar to that observed in the triple KO of the APP family members, APP, APLP1, and APLP2 (27).…”

Section: The Phenotype Of Fe65 Null Animalssupporting

confidence: 78%

“…This hypothesis is supported by further observations indicating that Fe65 and APP are also present in growth cones and synapses, mostly at the level of actin-rich lamellipodia (39). The neuropathological phenotype of the Fe65/Fe65L1 (26) DKO mice and those of the triple KO of APP/APLP1/APLP2 (27) or Mena/VASP/EVL (36) could be interpreted as defects of cell movement, thus confirming the possible role of Fe65 in this function. The Drosophila orthologs of the mammalian Mena and mDab1 genes are genetic modulators of the phenotype observed in flies null for the Abl tyrosine kinase.…”

Section: Fe65 Cytoskeleton Remodeling and Cell Movementsupporting

confidence: 61%

See 1 more Smart Citation

Fe65 matters: New light on an old molecule

et al. 2012

View full text Add to dashboard Cite

SummaryThe discovery that the main constituents of amyloid deposits, characteristic of Alzheimer neuropathology, derive from the proteolytic processing of the membrane precursor amyloid precursor protein (APP) is one of the milestones of the research history of this disease. Despite years of intense studies, the functions of APP and of its amyloidogenic processing are still under debate. One focus of these studies was the complex network of protein-protein interactions centered at the cytosolic domain of APP, which suggests the involvement of APP in a lively signaling pathway. Fe65 was the first protein to be demonstrated to interact with the APP cytodomain. Starting from this observation, a large body of data has been gathered, indicating that Fe65 is an adaptor protein, which binds numerous proteins, further than APP. Among these proteins, the crosstalk with Mena, mDab, and Abl suggested the involvement of the Fe65-APP complex in the regulation of cell motility, with a relevant role in differentiation and development. Other partners, like the histone acetyltransferase Tip60, indicated the possibility that the nuclear fraction of Fe65 could be involved in gene regulation and/or DNA repair.2012 IUBMB IUBMB Life, 64(12): 936-942, 2012

show abstract

Section: The Phenotype Of Fe65 Null Animalssupporting

confidence: 78%

Section: Fe65 Cytoskeleton Remodeling and Cell Movementsupporting

confidence: 61%

Fe65 matters: New light on an old molecule

et al. 2012

View full text Add to dashboard Cite

show abstract

“…WT, PS1‐KO, PS2‐KO, and PS1/2‐DKO (called PS‐DKO) mouse MEFs were provided by Dr. Bart De Strooper (University of Leuven). APP/APLP2‐KO (called APP‐DKO) (Herms et al , 2004) and PS1‐KI M146V knock‐in mice (Guo et al , 1999). All experiments were performed according to a protocol approved by the Institutional Animal Care and Use Committee of the Columbia University Medical Center and were consistent with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.…”

Section: Methodsmentioning

confidence: 99%

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

et al. 2017

View full text Add to dashboard Cite

In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β‐secretase to generate a 99‐aa C‐terminal fragment (C99) that is then cleaved by γ‐secretase to generate the β‐amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ‐secretase activity is enriched in mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM) and that ER–mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ‐secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.

show abstract

“…There are, however, a number of experimental observations suggesting that the APP family of proteins might play a role in regulating cell adhesion. For example, most triple knock-out mice developed cortical dysplasias, a condition that could result from defects in the adhesion of migrating neurons to extracellular matrix (4). Overexpression of apl-1 in the worm caused organ detachment (7), and transgenic flies expressing human APP developed a blistered-wing phenotype (12).…”

mentioning

confidence: 99%

Structural Characterization of the E2 Domain of APL-1, a Caenorhabditis elegans Homolog of Human Amyloid Precursor Protein, and Its Heparin Binding Site

Hoopes

Liu

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The amyloid ␤-peptide deposit found in the brain tissue of patients with Alzheimer disease is derived from a large heparinbinding protein precursor APP. The biological function of APP and its homologs is not precisely known. Here we report the x-ray structure of the E2 domain of APL-1, an APP homolog in Caenorhabditis elegans, and compare it to the human APP structure. We also describe the structure of APL-1 E2 in complex with sucrose octasulfate, a highly negatively charged disaccharide, which reveals an unexpected binding pocket between the two halves of E2. Based on the crystal structure, we are able to map, using site-directed mutagenesis, a surface groove on E2 to which heparin may bind. Our biochemical data also indicate that the affinity of E2 for heparin is influenced by pH: at pH 5, the binding appears to be much stronger than that at neutral pH. This property is likely caused by histidine residues in the vicinity of the mapped heparin binding site and could be important for the proposed adhesive function of APL-1. Amyloid precursor protein (APP)3 belongs to a gene family that in mammals includes two additional members, APLP1 and APLP2 (1-3). This gene family is important for viability because mice lacking all three members die shortly after birth (4). The function of APP and APP-like proteins and why their loss causes death are, however, not clear. Rare mutations in the human APP gene are also known to cause familial Alzheimer disease (for a review, see Ref. 5). The nematode Caenorhabditis elegans has a single APP-related gene, apl-1 (6). Inactivation of apl-1 prevents proper molting, a process that allows the worm to shed old cuticles between larval stages, and causes several other morphological defects (7).APP and APP-related proteins are type I membrane proteins. The majority of the full-length protein resides on the extracellular side of the membrane (Fig. 1A), and contains two conserved domains (E1, E2). E1 and E2 are retained in soluble forms of the protein, which are proteolytically released from the membrane by secretases. So far neither the primary sequence nor the three-dimensional structure of these two conserved domains has revealed any homology that would allow a convincing assignment of biological function to APP (8 -11). There are, however, a number of experimental observations suggesting that the APP family of proteins might play a role in regulating cell adhesion. For example, most triple knock-out mice developed cortical dysplasias, a condition that could result from defects in the adhesion of migrating neurons to extracellular matrix (4). Overexpression of apl-1 in the worm caused organ detachment (7), and transgenic flies expressing human APP developed a blistered-wing phenotype (12). Furthermore, in cell cultures, APP appears to concentrate to sites of adhesion (13-15).The structure of human E2/CAPPD has been solved by x-ray crystallography and NMR (10,11,22). In the x-ray structure, which contains the entire E2 region, the molecule forms a headto-tail dimer (10). This observation ...

show abstract

Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members

Cited by 293 publications

References 51 publications

Fe65 matters: New light on an old molecule

Fe65 matters: New light on an old molecule

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Structural Characterization of the E2 Domain of APL-1, a Caenorhabditis elegans Homolog of Human Amyloid Precursor Protein, and Its Heparin Binding Site

Contact Info

Product

Resources

About