Selective PrP‐like protein, doppel immunoreactivity in dystrophic neurites of senile plaques in Alzheimer's disease

Ferrer, Isidre; Freixas, M.; Blanco, R.; Carmona, Margarita; Puig, Berta

doi:10.1111/j.1365-2990.2003.00534.x

Cited by 15 publications

(15 citation statements)

References 38 publications

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“…In addition, the up-regulation of astrocyte-specific genes in PrP-deficient mice ectopically expressing Dpl, has suggested that Dpl is actively involved in glial cell activation in the brain (46). Recently, however, Ferrer and collaborators described a Dpl accumulation in abnormal neurites of senile plaques, probably originated from impaired transport and subcellular localization or by an anomalous turnover of the protein (20). Similarly, tumor astrocytes exhibited a Dpl accumulation within the cells, that seems associated with the WHO astrocytoma malignancy grades (Chiarelli and Valentini, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, the expression of the doppel gene has been investigated in other pathological contexts. Ferrer and collaborators (20) have recently reported a selective Dpl immunoreactivity in dystrophic neuritis in Alzheimer's disease patients. In tumors, the first evidence of a possible implication of Dpl has been recently produced by our group, reporting an aberrant PRND expression in the astrocytic and leukaemic specimens with different malignancy grades (21,22).…”

Section: Introductionmentioning

confidence: 98%

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Nuclear mRNA retention and aberrant doppel protein expression in human astrocytic tumor cells

et al. 2006

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Abstract. Doppel (Dpl) is a paralogue of the mammalian Prion (PrP) protein. It is abundant in testis and, unlike PrP, it is expressed at low levels in the adult central nervous system (CNS). Besides, Dpl overexpression correlates with some prion-disease pathological features, such as ataxia and death of cerebellar neurons. Recently, ectopic expression of doppel was found in two different tumor types, specifically in glial and haematological cancers. In this study the doppel gene (PRND) mRNA and protein expression in PRT-HU2 and IPDDC-A2 astrocytoma-derived cell lines was investigated. Northern blot analysis revealed two equally abundant PRND mRNA isoforms, while real-time PCR, on nuclear and cytoplasmic RNA fractions, and cRNA in situ hybridization, on astrocytoma cells and bioptical specimens, showed a nuclear retention of PRND transcripts. Western blot analysis showed that the amount of protein expressed is low compared to the level of mRNA. Moreover deglycosylation studies indicated that Dpl undergoes unusual glycosylation processes. Immunohistochemistry experiments demonstrated that Dpl was mainly localised in the cytoplasm of the astrocytic tumor cells, and that it failed to be GPI-anchored to the cell membrane. This unusual cellular localization was also confirmed through EGFP-Dpl expression in astrocytomas; on the contrary, HeLa cells exhibited the expected Dpl membrane localization. Our findings suggest an aberrant doppel gene expression pattern, characterized by a substantial nuclear retention of the transcript, an altered post-translational modification of the protein and an unusual cytoplasmic localization. IntroductionIn 1999, the first prion-gene paralogue, doppel (PRND), was described in rodents (1,2). Subsequently, the doppel gene was confirmed in humans (3), cattle, sheep (4), and goats (5). Comparative gene expression analysis was reported on different patterns of temporal and spatial expression among prion and doppel. Thus, whereas prion protein (PrP) is widely expressed, showing the highest expression profiles within the CNS (6), doppel shows barely detectable levels in most tissue (4,7). Doppel protein (Dpl) was found highly expressed only in adult and fetal testis (8), and different groups recently proposed an involvement in male gametogenesis (9-11). Based on the structural similarities between PrP (12) and Dpl (13), a role of doppel in the development of prion neurodegenerative diseases was hypothesised (14). Specifically, when ectopically expressed in some Prnp 0/0 transgenic lines, Dpl causes Purkinje cell death and ataxia (reviewed in ref. 15). However, Dpl-induced neurodegeneration can be rescued by the introduction of a Prnp transgene (16), suggesting the possibility that the protein interacts or competes with PrP in a sort of molecular antagonism-model (17). Further studies were performed to demonstrate a direct involvement of doppel in prion-diseases in humans (7) as well as in animals (18,19). From these analyses, doppel seems not to be associated with the diseases, neither if one ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Nuclear mRNA retention and aberrant doppel protein expression in human astrocytic tumor cells

et al. 2006

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“…However, opposite to AD, in sCJD increased levels of BACE1 activity in CSF did not correlate with higher levels of BACE1 protein in brain. Since amyloid plaques have been detected in sCJD brain patients [49]–[51], these results suggest a disturbed Aβ metabolism in sCJD [42], [52], [53].…”

Section: Discussionmentioning

confidence: 73%

A Common BACE1 Polymorphism Is a Risk Factor for Sporadic Creutzfeldt-Jakob Disease

et al. 2012

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The β site APP cleaving enzyme 1 (BACE1) is the rate-limiting β-secretase enzyme in the amyloidogenic processing of APP and Aβ formation, and therefore it has a prominent role in Alzheimer’s disease (AD) pathology. Recent evidence suggests that the prion protein (PrP) interacts directly with BACE1 regulating its β-secretase activity. Moreover, PrP has been proposed as the cellular receptor involved in the impairment of synaptic plasticity and toxicity caused by Aβ oligomers. Provided that common pathophysiologic mechanisms are shared by Alzheimer’s and Creutzfeldt-Jakob (CJD) diseases, we investigated for the first time to the best of our knowledge a possible association of a common synonymous BACE1 polymorphism (rs638405) with sporadic CJD (sCJD). Our results indicate that BACE1 C-allele is associated with an increased risk for developing sCJD, mainly in PRNP M129M homozygous subjects with early onset. These results extend the very short list of genes (other than PRNP) involved in the development of human prion diseases; and support the notion that similar to AD, in sCJD several loci may contribute with modest overall effects to disease risk. These findings underscore the interplay in both pathologies of APP, Aβ oligomers, ApoE, PrP and BACE1, and suggest that aging and perhaps vascular risk factors may modulate disease pathologies in part through these key players.

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“…The relationship between the PrPC and physiopathological mechanisms of Alzheimer's disease (AD) is well understood [23][24][25][26][27][28][29]. On our part, we have observed a particular behaviour of PrPC in brains with AD.…”

Section: Introductionmentioning

confidence: 68%

Cellular Prion Protein and Sexual Dimorphic Areas in Rodents. Correlates with Alzheimer Disease

Cuadrado‐Tejedor¹,

Irujo²,

Paternain³

et al. 2011

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Selective PrP‐like protein, doppel immunoreactivity in dystrophic neurites of senile plaques in Alzheimer's disease

Cited by 15 publications

References 38 publications

Nuclear mRNA retention and aberrant doppel protein expression in human astrocytic tumor cells

Nuclear mRNA retention and aberrant doppel protein expression in human astrocytic tumor cells

A Common BACE1 Polymorphism Is a Risk Factor for Sporadic Creutzfeldt-Jakob Disease

Cellular Prion Protein and Sexual Dimorphic Areas in Rodents. Correlates with Alzheimer Disease

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