Direct Binding of Reelin to VLDL Receptor and ApoE Receptor 2 Induces Tyrosine Phosphorylation of Disabled-1 and Modulates Tau Phosphorylation

Hiesberger, Thomas; Trommsdorff, M.; Howell, Brian W.; Goffinet, André M.; Mumby, Marc C.; Cooper, Jonathan A.; Herz, Joachim

doi:10.1016/s0896-6273(00)80861-2

Cited by 843 publications

(681 citation statements)

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“…Reelin is a large extracellular glycoprotein secreted by Cajal-Retzius cells and mediating proper positioning of neurons during development through the activation of the apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR, (D'Arcangelo et al, 1995Hiesberger et al, 1999;Howell et al, 1997;Tommsdorff et al, 1999). Transduction of the signal involves the interaction of the adapter protein Dab1 with the intracellular NPxY motiv of these receptors, resulting in tyrosine phosphorylation of Dab1, activation of Src family of non-receptor tyrosine kinases, and triggering a downstream cytosolic kinase cascade beginning with the activation of phosphatidylinositol-3-kinase (PI3K) and ending with the inhibition of glycogen synthase kinase 3β (GSK3β; for recent review, see Herz and Cheng, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…This most common type of dementia is characterized by progressive cognitive decline and two histopathological hallmarks including amyloid-beta (Αβ) plaques, which are caused by an imbalance in Aβ metabolism, and neurofibrillary tangles that result from abnormal phosphorylation and aggregation of Tau (Glenner and Wong, 1984;Grundke-Iqbal et al, 1986). Reelin binding to its receptors potently downregulates the activity of GSK3β, a major Tau kinase, and as a result mutant mice with defects in the Reelin signaling show increased levels of hyperphosphorylated Tau (Beffert et al, 2004;Hiesberger et al, 1999;Ohkubo et al, 2003). In addition, the Reelin receptors are also targets of the common ApoE isoform ε4, a major genetic risk factor associated with sporadic AD (Corder et al, 1993;Schmechel et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Age-related accumulation of Reelin in amyloid-like deposits

Knuesel

Nyffeler

Mormède

et al. 2009

Neurobiology of Aging

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Age-related accumulation of Reelin in amyloid-like deposits Abstract Accumulating evidence suggest that alterations in Reelin-mediated signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Abeta species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD. ABSTRACTAccumulating evidence suggest that alterations in Reelin-mediated signalling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits.These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Aβ species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD.3

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Age-related accumulation of Reelin in amyloid-like deposits

Knuesel

Nyffeler

Mormède

et al. 2009

Neurobiology of Aging

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“…39 Reelin serves a dual purpose in the mammalian brain: it is crucial to the correct cytoarchitecture of laminated structures during embryonic development 18,40 and modulates dendritic growth and synaptic plasticity at post-natal and adult stages. 41,42 These activities are, at least in part, mediated by binding to apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR), [43][44][45] resulting in phosphorylation of the intracellular adaptor protein protein disabled homolog 1 (DAB1). [46][47][48] Phosphorylated DAB1 activates several different signaling pathways involved in formation and plasticity of neuronal networks (for review, see ref.…”

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confidence: 99%

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

Dazzo

Fanciulli²,

Serioli

et al. 2015

The American Journal of Human Genetics

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Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.Temporal-lobe epilepsy is the most common type of focal epilepsy. It is sometimes associated with structural brain lesions, but genetic forms have also been described. Familial temporal-lobe epilepsy comprises two genetically distinct syndromes: familial mesial temporal-lobe epilepsy (FMTLE [MIM: 611630]) 1 and autosomal-dominant lateral temporal epilepsy (ADLTE [MIM: 600512]), also named autosomal-dominant partial epilepsy with auditory features (ADPEAF). 2 ADLTE is a well-defined epileptic syndrome clinically characterized by focal seizures with prominent auditory and/or aphasic symptoms, normal brain MRI, and relatively benign evolution. 2,3 Its inheritance pattern is autosomal dominant with reduced penetrance (around 70%). Mutations associated with ADLTE are found in leucine-rich, glioma inactivated 1 (LGI1 [MIM: 604619]) 4-6 in 30%-50% of ADLTE-affected families. 3,7,8 Other genes harboring ADLTE-causing mutations are unknown.LGI1 is expressed mainly in neurons, particularly in the neocortex and limbic regions, 4,9 and its protein product, LGI1, is secreted. 9 LGI1 has been implicated in the transmission of K þ and AMPA synaptic currents 10,11 and in the regulation of post-natal maturation of cortical excitatory synapses and dendrite pruning. 12 However, it is not known which of these functions underlies ADLTE. Identification of additional genes whose mutations cause ADLTE will help to clarify the pathoge...

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“…11 Reelin binds several proteins as likely receptors, including apolipoprotein E receptor 2 (ApoER2), very-low-density lipoprotein receptor (VLDL-R) and a3b1 integrin protein. [12][13][14] Reelin binding to ApoER2 and VLDLR receptors induces clustering of the latter receptors, causing dimerization/oligomerization of the adaptor protein, disabled-1 (Dab-1), on the cytosolic aspect of the plasma membrane 15 with eventual tyrosine phosphorylation of Dab-1 adapter protein, 16 facilitating the transduction of signaling pathway from the Reelin-producing cells (GABAergic neurons 17 or Cajal-Retzius cells of layer I) 18 to downstream receptor sites on cortical pyramidal cells. 19 In vivo, Reelin is processed by cleavage at two locations, that is, between repeats 2 and 3 and repeats 6 and 7, 20 resulting in three final fragments.…”

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confidence: 99%