3 November 2003. A paper in last Friday's Science reports that autosomal-dominant Parkinson's disease can be caused not only by α-synuclein mutations, but also by a triplication of a fragment of DNA containing the gene. This result suggests that dosage of α-synuclein may be the key factor in pathogenesis.
Andrew Singleton, at the National Institute on Aging, together with colleagues there, at other branches of the NIH, the Mayo Clinics, and Georgetown University Medical Center, Washington, DC, found the triplication when they were searching for the genetic cause of inherited Parkinson's in an extended family with normal copies of the synuclein gene. Initially, haplotype analysis linked affected family members to the gene for PARK4, but when a member without this haplotype showed symptoms of the disease, the authors looked for linkage at a higher resolution. Singleton and colleagues found that the disease was, in fact, linked to a 26 cMorgan region of chromosome 4 which harbors the synuclein gene, leaving them back where they had started. When the authors resequenced this section of DNA, they found that there were no pathogenic mutations. Furthermore, heterozygous single nucleotide polymorphisms known to exist near the beginning and end of the synuclein gene were present in family members with the disease, effectively ruling out the possibility of a whole gene deletion.
The mystery cleared up when the authors found that some synuclein intragenic markers were inherited in a non-Mendelian fashion that hinted at multiple gene copies. Using real-time quantitative PCR, Singleton was able to show that synuclein exons had indeed undergone a triplication. Fluorescence in-situ hybridization using probes to the gene confirmed this finding. Quantitative PCR allowed the authors to map the extent of the triplication; it covers about 2 Mbp of DNA and contains 17 annotated genes. The authors entertain the possibility that one of the other 16 genes rather than α-synuclein may be responsible for the disease, or that interruption of the flanking sequences may be pathogenic, but favor increased dosage of synuclein as the most parsimonious explanation. If this proves to be true, the etiology of PD would seem to resemble more closely that of Alzheimer's disease (AD), where FAD mutations are thought to lead to increased APP cleavage, and Down's syndrome, where chromosome 21 trisomy leads to abnormally high expression of the amyloid β precursor protein (see ARF related news story).
This is not the only parallel with AD. In the October FASEB Journal, a report penned by coauthors on the Science paper suggests that α-synuclein, like Aβ, can be released from neurons into the cerebrospinal fluid and from there to the plasma. When Omar El-Agnaf, Sultan Salem and colleagues at the University of Lancaster, England, examined neuronal cultures with a battery of antibodies designed to distinguish α-synuclein from β- and γ-synuclein, they found that α-synuclein is secreted into the medium. Furthermore, they also find the protein in human plasma and cerebrospinal fluid. α-synuclein does not have a signal sequence for targeting the nascent protein to the ER and hence providing a means to export it from the cell. Nevertheless, El-Agnaf's data raise the possibility of using CSF or plasma levels of synuclein as a biomarker for PD in the future. In these early studies, the authors found no significant difference between synuclein levels in plasma from Parkinson's patients and controls.—Tom Fagan.
Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K. alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003 Oct 31;302(5646):841. No abstract available.
El-Agnaf OM, Salem SA, Paleologou KE, Cooper LJ, Fullwood NJ, Gibson MJ, Curran MD, Court JA, Mann DM, Ikeda S, Cookson MR, Hardy J, Allsop D. Alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma.
FASEB J. 2003 Oct;17(13):1945-7. Epub 2003 Aug 15.