Comparison of kindreds with parkinsonism and α‐synuclein genomic multiplications

TLDR

Genomic triplication of the alpha‑synuclein gene has been linked to familial Parkinson’s disease, as seen in the Spellman‑Muenter kindred. This study reports an independent Swedish‑American family with early‑onset parkinsonism and dementia caused by alpha‑synuclein triplication. Brain tissue from affected members of both kindreds was examined to compare clinical, pathological, and biochemical phenotypes. Brain mRNA and soluble protein analyses show a two‑fold increase in alpha‑synuclein expression, and hippocampal CA2/3 neuronal loss is a hallmark of this inherited parkinsonism, underscoring the broader implications of alpha‑synuclein overexpression for idiopathic synucleinopathies.

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.