. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9. PubMed.

Recommends

Please login to recommend the paper.

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. In recent months, the field of Parkinson disease (PD) has seen several exciting research developments. Three papers address increased α-synuclein (αS) expression in the human brain as a neurotoxic event in the pathogenesis of this disorder; one additional paper identifies a probable susceptibility gene for sporadic PD, and a fifth highlights the importance of the protective function of the parkin gene in an in vivo rat model of αS-mediated toxicity.

    As a mostly presynaptic protein, αS is transcribed from five of the six exons of the SNCA gene and represents one of the most abundant proteins found in the adult nervous system. In the first of a series of five publications, Chartier-Harlin et al. last fall reported that a rare duplication event of the SNCA gene on one chromatid of chromosome 4, leading to a total of three SNCA gene copies, lies at the root of an aggressive Parkinsonian phenotype that encompasses early onset PD with cognitive and autonomic dysfunction transmitted in an autosomal-dominant fashion. This report further strengthens the importance of the gene dosage effect of the SNCA gene in the pathogenesis of rare familial forms of the disorder, which was previously raised by two independent reports of triplication events in the SNCA gene (leading to a total of four copies) (Singleton et al., 2003; Farrer et al., 2004). Intriguingly, the copy number of the SNCA gene, its resultant transcription, and the severity of the phenotype appeared to correlate with the gene dosage in all these cases. That is consistent with the concept of a toxic gain-of-function effect of wild-type αS in this class of disorders that are generally referred to as "synucleinopathies."

    Gispert et al., 2005 demonstrated that gene dosage changes were not found as the underlying mutant genotype in a European cohort of familial PD phenotypes from Germany, Portugal, and the former Yugoslavia. Thus, as expected, these multiplication events of the SNCA gene are (and will likely remain) rare and isolated contributors to the phenotype of PD. Even so, they may be just as significant to the understanding of PD pathology as APP gene dosage in Down syndrome is to the development of Alzheimer disease pathology.

    The third paper discussed in this comment fits in logical succession with the body of work on gene dosage. It revisits the genetics of the SNCA promoter as a susceptibility factor for sporadic (not familial) PD (Pals et al., 2004). In it, Matt Farrer, Christine van Broeckhoven, and colleagues first confirmed previous reports that had postulated an association between the SNCA promoter and sporadic PD. In addition, the authors also characterized a "minimum promoter haplotype" of 15,338 bp that is overrepresented in their cohort of 175 patients from Belgium and that may act as a susceptibility factor for PD development. The implication from such a positive association of a distinct SNCA promoter haplotype with sporadic PD is that the expression levels of the αS protein would be increased in vivo in contrast to an allele carrying a promoter haplotype not associated with PD. This hypothesis can now be tested in detail in cellular promoter activity assays, as used, for example, by Chiba-Falek and Nussbaum in the past.

    A fourth study provides additional genetic input to the list of susceptibility factors in sporadic PD. Ellen Sidransky and her colleagues at the NIH (Varkonyi et al., 2003) first observed Parkinsonism in a subgroup of patients with a genetically defined glycosphingolipid storage disorder called Gaucher’s disease. Last November, Aharon-Peretz et al. added further evidence to this association when they reported a statistically significant occurrence of gene mutations in the glucocerebrosidase-encoding gene (GBA) among Ashkenazi Jews with sporadic PD who showed no signs of Gaucher’s disease (Aharon-Peretz et al., 2004). In their study, 31 percent of sporadic PD patients had either one or two mutant GBA alleles, in contrast to only 4 percent of people with sporadic Alzheimer disease. The underlying molecular pathway between altered GBA genotypes and the development of PD remains to be determined, in particular whether glucocerebrosidase activity (which, when absent, results in Gaucher’s disease phenotype) intersects with other known PD-associated gene products.

    Lastly, the fifth paper, by Patrick Aebischer’s group, provides an intriguing animal model by pairing the authors’ previously developed toxic in vivo model of human αS overexpression by lentiviral delivery with the neuroprotective effects of the concomitant delivery of wild-type parkin (LoBianco et al., 2004). Numerous studies have linked the latter protein to monogenic forms of PD in a loss-of-function type (e.g., Hedrich et al., 2002). Many researchers see overexpression of neural parkin as a valid therapeutic goal to confer protection of dopaminergic cells from PD-related insults. The Aebischer group demonstrated just that by showing a significant reduction of mutant, human αS (A30P)-induced neuronal loss in the nigrostriatal pathway by parkin overexpression. In association with this neuroprotection, they observed an increase in αS-positive inclusions. It remains unknown which mechanism underlies the significant protection of the dopamine-producing cells in this rat model, and whether parkin intersects with αS metabolism directly or indirectly. Even so, the authors suggested that these results were consistent with a contributing role for parkin in inclusion (Lewy body) formation in vivo, as has been suggested by past immunohistochemical studies in human PD tissue (Schlossmacher et al., 2002).

    Together, these studies highlight three issues:

    1. steady-state levels of αS are important in the pathogenesis of PD in the adult human brain, and multiple pathways potentially contribute to its control;

    2. an important question is whether the nucleotide sequence, the rate of transcription, or the protein product of the SNCA gene could serve as a biomarker for PD;

    3. the concept of increased parkin expression is being validated as a therapeutic target; this goal is of equal importance to the desired downregulation of α-synuclein expression in vivo.

    References:

    . Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9. PubMed.

    . alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003 Oct 31;302(5646):841. PubMed.

    . Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol. 2004 Feb;55(2):174-9. PubMed.

    . Failure to find alpha-synuclein gene dosage changes in 190 patients with familial Parkinson disease. Arch Neurol. 2005 Jan;62(1):96-8. PubMed.

    . alpha-Synuclein promoter confers susceptibility to Parkinson's disease. Ann Neurol. 2004 Oct;56(4):591-5. PubMed.

    . Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet. 2001 Dec 15;10(26):3101-9. PubMed.

    . Gaucher disease associated with parkinsonism: four further case reports. Am J Med Genet A. 2003 Feb 1;116A(4):348-51. PubMed.

    . Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2004 Nov 4;351(19):1972-7. PubMed.

    . Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17510-5. PubMed.

    . Evaluation of 50 probands with early-onset Parkinson's disease for Parkin mutations. Neurology. 2002 Apr 23;58(8):1239-46. PubMed.

    . Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. Am J Pathol. 2002 May;160(5):1655-67. PubMed.