MovDisordV3, Main, Exploration, bibRecord, 001074

Leucine-Rich Repeat Kinase 2 and Alternative Splicing in Parkinson's Disease

Identifieur interne : 001074 ( Main/Exploration ); précédent : 001073; suivant : 001075

Leucine-Rich Repeat Kinase 2 and Alternative Splicing in Parkinson's Disease

Auteurs : David A. Elliott [Australie] ; Woojin S. Kim [Australie] ; Sarsha Gorissen [Australie] ; Glenda M. Halliday [Australie] ; John B. J. Kwok [Australie]

Source :

Movement disorders [ 0885-3185 ] ; 2012.

RBID : Pascal:12-0315955

Descripteurs français

Pascal (Inist)
- Maladie de Parkinson, Pathologie du système nerveux, Leucine, Kinase, Epissage, Protéine tau.

English descriptors

KwdEn :
- Kinase, Leucine, Nervous system diseases, Parkinson disease, Splicing, Tau protein.

Abstract

Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD) and are associated with pleiomorphic neuropathology. We hypothesize that LRRK2 mediates its pathogenic effect through alternative splicing of neurodegeneration genes. Methods used in this study included western blotting analysis of subcellular protein fractions, exon-array analysis of RNA from cultured neuroblastoma cells transfected with LRRK2 expression vectors, and reverse-transcription polymerase chain reaction (RT-PCR) of RNA from cultured cells and postmortem tissue. Overexpression of the LRRK2 G2019S mutant resulted in a significant (2.6-fold; P = 0.020) decrease in nuclear transactive response DNA-binding protein 43 levels. Exon-array analyses revealed that wild-type LRRK2 had a significant effect on the expression of genes with nuclear (P < 10-²²) and cell-cycle functions (P < 10^-15). We replicated changes in gene expression in 30% of selected genes by quantitative RT-PCR. Overexpression of LRRK2 resulted in the altered splicing of two genes associated with PD, with an increased inclusion of exon 10 of microtubule-associated protein tau (1.7-fold; P = 0.001) and exon 5 of the alpha-synuclein (SNCA) gene (1.6-fold; P =0.005). Moreover, overexpression of LRRK2 (G2019S) and two mutant genes associated with neurodegeneration, TARDBP (M337V) and FUS (R521H), were associated with decreased inclusion out of the dystonin (DST) 1e precursor exons in SK-N-MC cells. Altered splicing of SNCA (1.9-fold; P < 0.001) and DST genes (log₂ 2.3-fold; P = 0.005) was observed in a cohort of PD, compared with neurologically healthy, brains. This suggests that aberrant RNA metabolism is an important contributor to idiopathic PD.

Affiliations:

Australie

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Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Kinase</term>
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<front><div type="abstract" xml:lang="en">Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD) and are associated with pleiomorphic neuropathology. We hypothesize that LRRK2 mediates its pathogenic effect through alternative splicing of neurodegeneration genes. Methods used in this study included western blotting analysis of subcellular protein fractions, exon-array analysis of RNA from cultured neuroblastoma cells transfected with LRRK2 expression vectors, and reverse-transcription polymerase chain reaction (RT-PCR) of RNA from cultured cells and postmortem tissue. Overexpression of the LRRK2 G2019S mutant resulted in a significant (2.6-fold; P = 0.020) decrease in nuclear transactive response DNA-binding protein 43 levels. Exon-array analyses revealed that wild-type LRRK2 had a significant effect on the expression of genes with nuclear (P < 10-<sup>22</sup>
) and cell-cycle functions (P < 10<sup>-15</sup>
). We replicated changes in gene expression in 30% of selected genes by quantitative RT-PCR. Overexpression of LRRK2 resulted in the altered splicing of two genes associated with PD, with an increased inclusion of exon 10 of microtubule-associated protein tau (1.7-fold; P = 0.001) and exon 5 of the alpha-synuclein (SNCA) gene (1.6-fold; P =0.005). Moreover, overexpression of LRRK2 (G2019S) and two mutant genes associated with neurodegeneration, TARDBP (M337V) and FUS (R521H), were associated with decreased inclusion out of the dystonin (DST) 1e precursor exons in SK-N-MC cells. Altered splicing of SNCA (1.9-fold; P < 0.001) and DST genes (log<sub>2</sub>
 2.3-fold; P = 0.005) was observed in a cohort of PD, compared with neurologically healthy, brains. This suggests that aberrant RNA metabolism is an important contributor to idiopathic PD.</div>
</front>
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<tree><country name="Australie"><noRegion><name sortKey="Elliott, David A" sort="Elliott, David A" uniqKey="Elliott D" first="David A." last="Elliott">David A. Elliott</name>
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<name sortKey="Elliott, David A" sort="Elliott, David A" uniqKey="Elliott D" first="David A." last="Elliott">David A. Elliott</name>
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	Movement Disorders (revue)
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Movement Disorders (revue)

Leucine-Rich Repeat Kinase 2 and Alternative Splicing in Parkinson's Disease

Leucine-Rich Repeat Kinase 2 and Alternative Splicing in Parkinson's Disease

Source :

Descripteurs français

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri