A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease

Marcelo A. Alarcón, Matías A. Medina, Qubai Hu, Miguel E. Avila, Bernabé I. Bustos, Eduardo Pérez-Palma, Alexis Peralta, Paulina Salazar, Giorgia D. Ugarte, Ariel E. Reyes, George M. Martin, Carlos Opazo, Randall T. Moon, Giancarlo V. De Ferrari

Resultado de la investigación: Article

17 Citas (Scopus)

Resumen

We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 (LRP6) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 (LRP6Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/β-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6Δ3 isoform is a novel splice variant, which shows diminished Wnt/β-catenin signaling activity and might have a functional role in individuals with AD.

Idioma originalEnglish
PublicaciónNeurobiology of Aging
Volumen34
N.º6
DOI
EstadoPublished - 1 jun 2013

Huella dactilar

Low Density Lipoprotein Receptor-Related Protein-6
Alzheimer Disease
Genes
Catenins
Exons
Protein Isoforms
Messenger RNA
Brain
Nervous System Diseases
Single Nucleotide Polymorphism

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Citar esto

Alarcón, Marcelo A. ; Medina, Matías A. ; Hu, Qubai ; Avila, Miguel E. ; Bustos, Bernabé I. ; Pérez-Palma, Eduardo ; Peralta, Alexis ; Salazar, Paulina ; Ugarte, Giorgia D. ; Reyes, Ariel E. ; Martin, George M. ; Opazo, Carlos ; Moon, Randall T. ; De Ferrari, Giancarlo V. / A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease. En: Neurobiology of Aging. 2013 ; Vol. 34, N.º 6.
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title = "A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease",
abstract = "We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 (LRP6) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 (LRP6Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/β-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6Δ3 isoform is a novel splice variant, which shows diminished Wnt/β-catenin signaling activity and might have a functional role in individuals with AD.",
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Alarcón, MA, Medina, MA, Hu, Q, Avila, ME, Bustos, BI, Pérez-Palma, E, Peralta, A, Salazar, P, Ugarte, GD, Reyes, AE, Martin, GM, Opazo, C, Moon, RT & De Ferrari, GV 2013, 'A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease', Neurobiology of Aging, vol. 34, n.º 6. https://doi.org/10.1016/j.neurobiolaging.2012.11.004

A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease. / Alarcón, Marcelo A.; Medina, Matías A.; Hu, Qubai; Avila, Miguel E.; Bustos, Bernabé I.; Pérez-Palma, Eduardo; Peralta, Alexis; Salazar, Paulina; Ugarte, Giorgia D.; Reyes, Ariel E.; Martin, George M.; Opazo, Carlos; Moon, Randall T.; De Ferrari, Giancarlo V.

En: Neurobiology of Aging, Vol. 34, N.º 6, 01.06.2013.

Resultado de la investigación: Article

TY - JOUR

T1 - A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease

AU - Alarcón, Marcelo A.

AU - Medina, Matías A.

AU - Hu, Qubai

AU - Avila, Miguel E.

AU - Bustos, Bernabé I.

AU - Pérez-Palma, Eduardo

AU - Peralta, Alexis

AU - Salazar, Paulina

AU - Ugarte, Giorgia D.

AU - Reyes, Ariel E.

AU - Martin, George M.

AU - Opazo, Carlos

AU - Moon, Randall T.

AU - De Ferrari, Giancarlo V.

PY - 2013/6/1

Y1 - 2013/6/1

N2 - We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 (LRP6) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 (LRP6Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/β-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6Δ3 isoform is a novel splice variant, which shows diminished Wnt/β-catenin signaling activity and might have a functional role in individuals with AD.

AB - We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 (LRP6) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 (LRP6Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/β-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6Δ3 isoform is a novel splice variant, which shows diminished Wnt/β-catenin signaling activity and might have a functional role in individuals with AD.

KW - Alternative splicing

KW - Alzheimer's disease

KW - LRP6

KW - Wnt/β-catenin signaling

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U2 - 10.1016/j.neurobiolaging.2012.11.004

DO - 10.1016/j.neurobiolaging.2012.11.004

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JO - Neurobiology of Aging

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