Article

Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms.

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR)_S679 Neurologie & Thérapeutique Expérimentale, F-75013, Paris, France.
Archives of neurology (Impact Factor: 7.01). 02/2009; 66(1):102-8. DOI: 10.1001/archneurol.2008.555
Source: PubMed

ABSTRACT Genomic multiplications of the alpha-synuclein gene (SNCA) cause autosomal dominant Parkinson disease (ADPD). The aim of this study was to assess the frequency and phenotype of SNCA rearrangements in a large series of families with typical or atypical AD parkinsonism.
Patients were screened by the exon dosage of the SNCA gene. The genotype of patients and relatives carrying SNCA rearrangements, the size of the multiplied regions, and the centromeric and telomeric breakpoints were determined by microsatellite dosage and 250K Affymetrix Single Polymorphism Nucleotide microarrays (Affymetrix, Santa Clara, California).
Index cases and, whenever appropriate, relatives of 286 mainly European families with ADPD were screened.
Four of 264 families (1.5%) with typical ADPD carried duplications and 1 of 22 families (4.5%) with atypical AD parkinsonism carried a triplication of SNCA. Genotyping and dosage analyses showed that the multiplied regions were variable in size (0.42-5.29 megabase pairs), suggesting that SNCA multiplications occurred independently. Phenotype analyses showed that the severity of the disease correlated with the SNCA copy number, but not with the minimal number of multiplied genes (1 to 33). Haplotype analysis of polymorphic markers suggested that multiplication of the SNCA gene occurred by both interchromosomal and intrachromosomal rearrangement.
Our results suggest that SNCA rearrangements may be more frequent than point mutations in ADPD. Furthermore, our results indicate that the phenotype associated with SNCA multiplications correlates with the number of copies of the gene and provides the first insight into the mechanisms underlying SNCA multiplication.

0 Followers
 · 
118 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: alpha-Synuclein (alpha-syn) is a small lipid-binding protein involved in vesicle trafficking whose function is poorly characterized. It is of great interest to human biology and medicine because alpha-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson's disease (PD). We previously created a yeast model of alpha-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to alpha-syn expression. We also uncovered a core group of proteins with diverse activities related to alpha-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of alpha-syn also exhibits strong defects in mitochondrial function. Unlike our previous strain, genetic suppression of endoplasmic reticulum (ER)-to-Golgi trafficking alone does not suppress alpha-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of alpha-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced alpha-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of alpha-syn foci, re-established ER-to-Golgi trafficking and ameliorated alpha-syn-mediated damage to mitochondria. They also corrected the toxicity of alpha-syn in nematode neurons and in primary rat neuronal midbrain cultures. Remarkably, the compounds also protected neurons against rotenone-induced toxicity, which has been used to model the mitochondrial defects associated with PD in humans. That single compounds are capable of rescuing the diverse toxicities of alpha-syn in yeast and neurons suggests that they are acting on deeply rooted biological processes that connect these toxicities and have been conserved for a billion years of eukaryotic evolution. Thus, it seems possible to develop novel therapeutic strategies to simultaneously target the multiple pathological features of PD.
    Disease Models and Mechanisms 03/2010; 3(3-4):194-208. DOI:10.1242/dmm.004267 · 5.54 Impact Factor
  • Article: [Sclera].
    [Show abstract] [Hide abstract]
    ABSTRACT: The sclera is the skeleton of the eye. It defines the size of the eye, provides a stable support for its optical elements, and is essential to the achievement of a focused retinal image. The sclera provides attachment for the extraocular muscles and allows passage of vital structures such as the optic nerve, the arterial blood supply, and the venous drainage system. The overall elastic properties of the sclera neutralize short‐term fluctuations of the intraocular pressure. More specialized functions of the sclera are the drainage of aqueous humor and the mechanical support provided for the fibers of the optic nerve during their passage through the eye wall. Drainage of aqueous humor from the anterior chamber is controlled partly by a specialized part of the sclera, the trabecular meshwork, and partly by the uveoscleral route of which the final segment involves passive transscleral fluid transport. The lamina cribrosa is the specialized part of the sclera that provides mechanical support for the optic nerve as it leaves the eye.Disturbances in the biochemistry and biomechanical properties of the sclera can have severe consequences for the visual function by producing an eye that is not spherical, too long, too short, too rigid, or too elastic. Such disturbances can also interfere with the vascular supply of the eye, the control mechanisms of the intraocular pressure, or the resistance of the transscleral volume flow.
    Archives d'ophtalmologie et revue générale d'ophtalmologie 02/1973; 33(1):67-72.
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this note we consider the class of linear finite dimensional multirate operators in the general time-varying case and describe a way of parametrizing all stabilizing controllers for any plant in this class.