Neurofibrillary tangles of Alzheimer's disease brains contain 14-3-3 proteins

Layfield, Robert; Fergusson, J.; Aitken, Alastair; Lowe, James; Landon, Michael; Mayer, Roland

doi:10.1016/0304-3940(96)12598-2

Cited by 178 publications

(114 citation statements)

References 15 publications

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“…Evidence also has been presented that both ␣-synuclein and 14 -3-3 proteins function as chaperones (Souza et al, 2000); however, the involvement of these proteins in signaling pathways as well as their participation in the pathogenesis of neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's disease has also been described (Layfield et al, 1996;Polymeropoulos et al, 1997;Charles et al, 2000;). For example, ␣-synuclein immunoreactivity has been detected in inclusion bodies with aggregated, ubiquitinated huntingtin protein of HD patients and transgenic mice, suggesting that the redistribution of this protein to inclusions might influence disease progression (Charles et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, genetic studies have identified point mutations in the ␣-synuclein protein that cause familial Parkinson's disease and enhance the aggregation of this protein (Polymeropoulos et al, 1997;Conway et al, 1998). With regard to 14 -3-3, association of this class of proteins with neurofibrillary tan- gles in Alzheimer's disease brains has been reported (Layfield et al, 1996). Neurofibrillary tangles are formed from the hyperphosphorylated microtubule-associated tau protein, and there is evidence that the mitogen-activated protein kinase pathway is responsible, at least in part, for the phosphorylation of tau (Drewes et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

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Accumulation of Mutant Huntingtin Fragments in Aggresome-like Inclusion Bodies as a Result of Insufficient Protein Degradation

Waelter

Boeddrich

Lurz

et al. 2001

MBoC

588

459

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The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 glutamines), but not with a polyglutamine tract in the normal range (20 glutamines), form aggresome-like perinuclear inclusions in human 293 Tet-Off cells. These structures contain aggregated, ubiquitinated huntingtin exon 1 protein with a characteristic fibrillar morphology. Inclusion bodies with truncated huntingtin protein are formed at centrosomes and are surrounded by vimentin filaments. Inhibition of proteasome activity resulted in a twofold increase in the amount of ubiquitinated, SDS-resistant aggregates, indicating that inclusion bodies accumulate when the capacity of the ubiquitin-proteasome system to degrade aggregation-prone huntingtin protein is exhausted. Immunofluorescence and electron microscopy with immunogold labeling revealed that the 20S, 19S, and 11S subunits of the 26S proteasome, the molecular chaperones BiP/GRP78, Hsp70, and Hsp40, as well as the RNA-binding protein TIA-1, the potential chaperone 14 -3-3, and ␣-synuclein colocalize with the perinuclear inclusions. In 293 Tet-Off cells, inclusion body formation also resulted in cell toxicity and dramatic ultrastructural changes such as indentations and disruption of the nuclear envelope. Concentration of mitochondria around the inclusions and cytoplasmic vacuolation were also observed. Together these findings support the hypothesis that the ATP-dependent ubiquitin-proteasome system is a potential target for therapeutic interventions in glutamine repeat disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Accumulation of Mutant Huntingtin Fragments in Aggresome-like Inclusion Bodies as a Result of Insufficient Protein Degradation

Waelter

Boeddrich

Lurz

et al. 2001

MBoC

588

459

View full text Add to dashboard Cite

show abstract

“…Its apparent role is to target proteins in the Golgi for transport to late endosomes. The 14-3-3 protein, which has many similarities to the Parkinson disease-associated protein ␣-synuclein (87), is found in neurofibrillary tangles (88), binds to tau, and is involved in phosphorylation of tau by glycogen synthase kinase 3␤ (89,90). Glycogen synthase kinase 3␤, which is the principal enzyme involved in phosphorylating tau, is regulated by 14-3-3 (91).…”

Section: Discussionmentioning

confidence: 99%

Protection against β-Amyloid-induced Apoptosis by Peptides Interacting with β-Amyloid

Nelson

Alkon

2007

Journal of Biological Chemistry

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␤-Amyloid peptide produces apoptosis in neurons at micromolar concentrations, but the mechanism by which ␤-amyloid exerts its toxic effect is unknown. The normal biological function of ␤-amyloid is also unknown. We used phage display, coprecipitation, and mass spectrometry to examine the proteinprotein interactions of ␤-amyloid in normal rabbit brain in order to identify the biochemical receptors for ␤-amyloid. ␤-Amyloid was found to bind primarily to proteins involved in low density lipoprotein and cholesterol transport and metabolism, including sortilin, endoplasmic reticulum-Golgi intermediate compartment 2 (ERGIC2), ERGIC-53, steroid 5␣-reductase, and apolipoprotein B. ␤-Amyloid also bound to the C-reactive protein precursor, a protein involved in inflammation, and to 14-3-3, a protein that regulates glycogen synthase kinase-3␤, the kinase involved in tau phosphorylation. Of eight synthetic peptides identified as targets of ␤-amyloid, three were found to be effective blockers of the toxic effect of ␤-amyloid on cultured neuronal cells. These peptides bound to the hydrophobic region (residues 17-21) or to the nearby protein kinase C pseudo-phosphorylation site (residues 26 -30) of ␤-amyloid, suggesting that these may be the most critical regions for ␤-amyloid effector action and for aggregation. Peptides or other small molecules that bind to this region may protect against ␤-amyloid toxic effect by competitively blocking its ability to bind ␤-amyloid effector proteins such as sortilin and 14-3-3.

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“…They are critical for many brain functions, and are involved in several neurological diseases. 14-3-3 proteins are present in the neurofibrillary tangles associated with Alzheimer's disease 178 and may facilitate Tau hyperphosphorylation which contributes to tangle formation. 179,180 14-3-3 proteins, including 14-3-3e, also interact with a-synuclein 181 and may contribute to the pathogenesis of Parkinson's disease.…”

Section: Lis1 Ndel1 Nde1 and Disc1mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Neurofibrillary tangles of Alzheimer's disease brains contain 14-3-3 proteins

Cited by 178 publications

References 15 publications

Accumulation of Mutant Huntingtin Fragments in Aggresome-like Inclusion Bodies as a Result of Insufficient Protein Degradation

Accumulation of Mutant Huntingtin Fragments in Aggresome-like Inclusion Bodies as a Result of Insufficient Protein Degradation

Protection against β-Amyloid-induced Apoptosis by Peptides Interacting with β-Amyloid

The DISC locus in psychiatric illness

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