Comparative mapping of DNA markers from the familial Alzheimer disease and Down syndrome regions of human chromosome 21 to mouse chromosomes 16 and 17.

Cheng, Shirley V.; Nadeau, Joseph H.; Tanzi, Rudolph E.; Watkins, Paul C.; Jagadesh, Jayashree; Taylor, Benjamin A.; Haines, Jonathan L.; Sacchi, Nicoletta; Gusella, James F.

doi:10.1073/pnas.85.16.6032

Cited by 56 publications

(19 citation statements)

References 36 publications

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“…A␤ peptide is generated by proteolysis of the amyloid precursor protein (APP), which is the product of a gene located on human chromosome 21 and on mouse chromosome 16. APP is expressed in most mammalian tissues (2,3) and is present in at least 10 different spliced variants (4). In the brain, the major isoform generating A␤ is a peptide consisting of 695 residues that contains a single transmembrane domain (5).…”

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confidence: 99%

Amyloid Precursor Protein Family-induced Neuronal Death Is Mediated by Impairment of the Neuroprotective Calcium/Calmodulin Protein Kinase IV-dependent Signaling Pathway

Mbebi¹,

Sée²,

Mercken³

et al. 2002

Journal of Biological Chemistry

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The aberrant metabolism of ␤-amyloid precursor protein (APP) and the progressive deposition of its derived fragment ␤-amyloid peptide are early and constant pathological hallmarks of Alzheimer's disease. Because APP is able to function as a cell surface receptor, we investigated here whether a disruption of the normal function of APP may contribute to the pathogenic mechanisms in Alzheimer's disease. To this aim, we generated a specific chicken polyclonal antibody directed against the extracellular domain of APP, which is common with the ␤-amyloid precursor-like protein type 2. Exposure of cultured cortical neurons to this antibody (APP-Ab) induced cell death preceded by neurite degeneration, oxidative stress, and nuclear condensation. Interestingly, caspase-3-like protease was not activated in this neurotoxic action suggesting a different mode of cell death than classical apoptosis. Further analysis of the molecular mechanisms revealed a calpain-and calcineurindependent proteolysis of the neuroprotective calcium/ calmodulin-dependent protein kinase IV and its nuclear target protein cAMP responsive element binding protein. These effects were abolished by the G protein inhibitor pertussis toxin, strongly suggesting that APP binding operates via a GTPase-dependent pathway to cause neuronal death. Alzheimer's disease (AD)1 is a devastating neurodegenerative disorder characterized by deposition of ␤-amyloid (A␤) plaques, accumulation of intracellular neurofibrillary tangles, and neuronal cell loss (1). A␤ peptide is generated by proteolysis of the amyloid precursor protein (APP), which is the product of a gene located on human chromosome 21 and on mouse chromosome 16. APP is expressed in most mammalian tissues (2, 3) and is present in at least 10 different spliced variants (4). In the brain, the major isoform generating A␤ is a peptide consisting of 695 residues that contains a single transmembrane domain (5). Although the physiological role of APP is still unclear, several studies have suggested that it is implicated in important physiological functions of neurons, such as neurite outgrowth, synaptogenesis, cell substrate adhesion and neuronal survival (for review see Ref. 6).Up to now, most of the research has been focused on the toxicity of A␤ peptide related to AD. A␤ has been reported to exert a variety of toxic effects on neurons both in vitro (7,8) and in vivo (9). However, it has been reported that mice overproducing A␤1-42 extracellularly showed no neuronal loss (10), thus suggesting that A␤ peptide seems not to be the only constituent in neurotoxicity associated to AD. Previous studies have demonstrated that overexpression of full-length APP induced degeneration of postmitotic neurons derived from embryonal carcinoma cells (11). Moreover, intracellular accumulation of wild-type APP in the rat hippocampus caused a specific type of neuronal degeneration in vivo in the absence of extracellular A␤ deposition (12), and viral vector-mediated overexpression of wild-type APP induced apoptosis-like death of neurons...

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Amyloid Precursor Protein Family-induced Neuronal Death Is Mediated by Impairment of the Neuroprotective Calcium/Calmodulin Protein Kinase IV-dependent Signaling Pathway

Mbebi¹,

Sée²,

Mercken³

et al. 2002

Journal of Biological Chemistry

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“…Nevertheless, the location of this gene to chromosome 16 was well established by these data, and it appears that most of the bands hybridizing to this probe originate from a single chromo- GABPI3 An insert from a cDNA clone encoding GABPB 1-1 was amplified by PCR with flanking primers, Cho et al (1991). eData from Cheng et al (1988). fData from Chomey et al (1982).…”

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Molecular and genetic characterization of GABP beta.

Brousse¹,

Birkenmeier

King

et al. 1994

Genes Dev.

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This report outlines three observations relating to GABPI3 , a polypeptide constituent of the heterotetrameric transcription factor GABP. Evidence is presented showing that the mouse genome encodes two highly related GABPI3 polypeptides, designated GABPI31-1 and GABPI32-1. Genomic and eDNA copies of the newly defined Gabpb2 gene were cloned and characterized, providing the conceptually translated amino acid sequence of GABPI32-1. The genes encoding these two proteins, as well as GABPc~, were mapped to three unlinked chromosomal loci. Although physically unlinked, the patterns of expression of the three genes were strikingly concordant. Finally, the molecular basis of GABPI3 dimerization was resolved. Carboxy-terminal regions of the two GABPI3 polypeptides, which mediate dimerization, bear highly related primary amino acid sequences. Both sequences are free of oL-helix destabilizing residues and, when displayed on idealized c~-helical projections, reveal marked amphipathy. Two observations indicate that these regions adopt an a-helical conformation and intertwine as coiled-coils. First, the dimer-forming region of GABPI32-1 can functionally replace the leucine zipper of a bZIP transcription factor. Second, a synthetic peptide corresponding to this region shows distinctive helical properties when examined by circular dichroism spectroscopy. Finally, evidence is presented showing that GABPI31-1 and GABPI32-1 can heterodimerize through this carboxy-terminal domain, but neither protein can heterodimerize via the dimer-forming region of the bZIP protein C/EBPI3.

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“…Weaver (wv) is a missense point mutation in the Kcnj6 gene, which has been cloned and mapped to mouse chromosome 16 (Cheng et al 1988, Reeves et al 1989. The Kcnj6 gene encodes the subunit of the homotetrameric potassium channel GIRK2 (Whorton and MacKinnon 2013).…”

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confidence: 99%

Cerebellar cortex development in the weaver condition presents regional and age-dependent abnormalities without differences in Purkinje cells neurogenesis

Martí¹,

Santa-Cruz²,

Hervás³

et al. 2016

Acta Neurobiologiae Experimentalis

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Ataxias are neurological disorders associated with the degeneration of Purkinje cells (PCs). Homozygous weaver mice (wv/wv) have been proposed as a model for hereditary cerebellar ataxia because they present motor abnormalities and PC loss. To ascertain the physiopathology of the weaver condition, the development of the cerebellar cortex lobes was examined at postnatal day (P): P8, P20 and P90. Three approaches were used: 1) quantitative determination of several cerebellar features;2) qualitative evaluation of the developmental changes occurring in the cortical lobes; and 3) autoradiographic analyses of PC generation and placement.Our results revealed a reduction in the size of the wv/wv cerebellum as a whole, confirming previous results. However, as distinguished from these reports, we observed that quantified parameters contribute differently to the abnormal growth of the wv/wv cerebellar lobes.Qualitative analysis showed anomalies in wv/wv cerebellar cytoarchitecture, depending on the age and lobe analyzed. Such abnormalities included the presence of the external granular layer after P20 and, at P90, ectopic cells located in the molecular layer following several placement patterns. Finally, we obtained autoradiographic evidence that wild-type and wv/wv PCs presented similar neurogenetic timetables, as reported. However, the innovative character of this current work lies in the fact that the neurogenetic gradients of wv/wv PCs were not modified from P8 to P90. A tendency for the accumulation of late-formed PCs in the anterior and posterior lobes was found, whereas early-generated PCs were concentrated in the central and inferior lobes. These data suggested that wv/wv PCs may migrate properly to their final destinations. The extrapolation of our results to patients affected with cerebellar ataxias suggests that all cerebellar cortex lobes are affected with several age-dependent alterations in cytoarchitectonics. We also propose that PC loss may be regionally variable and not related to their neurogenetic timetables.

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Comparative mapping of DNA markers from the familial Alzheimer disease and Down syndrome regions of human chromosome 21 to mouse chromosomes 16 and 17.

Cited by 56 publications

References 36 publications

Amyloid Precursor Protein Family-induced Neuronal Death Is Mediated by Impairment of the Neuroprotective Calcium/Calmodulin Protein Kinase IV-dependent Signaling Pathway

Amyloid Precursor Protein Family-induced Neuronal Death Is Mediated by Impairment of the Neuroprotective Calcium/Calmodulin Protein Kinase IV-dependent Signaling Pathway

Molecular and genetic characterization of GABP beta.

Cerebellar cortex development in the weaver condition presents regional and age-dependent abnormalities without differences in Purkinje cells neurogenesis

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