title: Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications.
abstract: Genomic triplication of the alpha-synuclein gene recently has been associated with familial Parkinson's disease in the Spellman-Muenter kindred. Here, we present an independent family, of Swedish-American descent, with hereditary early-onset parkinsonism with dementia due to alpha-synuclein triplication. Brain tissue available from affected individuals in both kindreds provided the opportunity to compare their clinical, pathological, and biochemical phenotypes. Of note, studies of brain mRNA and soluble protein levels demonstrate a doubling of alpha-synuclein expression, consistent with molecular genetic data. Pathologically, cornu ammonis 2/3 hippocampal neuronal loss appears to be a defining feature of this form of inherited parkinsonism. The profound implications of alpha-synuclein overexpression for idiopathic synucleinopathies are discussed.
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA. farrer.matthew@mayo.edu
authors.forename: Matt
authors.initials: M
authors.lastname: Farrer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kachergus
authors.forename: Lysia
authors.initials: L
authors.lastname: Forno
authors.forename: Sarah
authors.initials: S
authors.lastname: Lincoln
authors.forename: Deng-Shun
authors.initials: DS
authors.lastname: Wang
authors.forename: Mary
authors.initials: M
authors.lastname: Hulihan
authors.forename: Demetrius
authors.initials: D
authors.lastname: Maraganore
authors.forename: Katrina
authors.initials: K
authors.lastname: Gwinn-Hardy
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Wszolek
authors.forename: Dennis
authors.initials: D
authors.lastname: Dickson
authors.forename: J William
authors.initials: JW
authors.lastname: Langston
mesh_terms: D001921:Brain / Q000473:pathology*; D004252:DNA Mutational Analysis; D004591:Electrophoresis, Polyacrylamide Gel; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009410:Nerve Degeneration / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein