title: Is Alpha-Synuclein Loss-of-Function a Contributor to Parkinsonian Pathology? Evidence from Non-human Primates.
abstract: Accumulation of alpha-synuclein (α-syn) in Lewy bodies and neurites of midbrain dopamine neurons is diagnostic for Parkinson's disease (PD), leading to the proposal that PD is a toxic gain-of-function synucleinopathy. Here we discuss the alternative viewpoint that α-syn displacement from synapses by misfolding and aggregation results in a toxic loss-of-function. In support of this hypothesis we provide evidence from our pilot study demonstrating that knockdown of endogenous α-syn in dopamine neurons of non-human primates reproduces the pattern of nigrostriatal degeneration characteristic of PD.
authors: Department of Translational Science & Molecular Medicine, Michigan State UniversityGrand Rapids, MI, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary'sGrand Rapids, MI, USA.
authors: Timothy J
authors: TJ
authors: Collier
authors: Departments of Psychiatry & Neurosurgery, Yale University School of MedicineNew Haven, CT, USA; Axion Research FoundationHamden, CT, USA.
authors: D Eugene
authors: DE
authors: Redmond
authors: Department of Translational Science & Molecular Medicine, Michigan State UniversityGrand Rapids, MI, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary'sGrand Rapids, MI, USA.
authors: Kathy
authors: K
authors: Steece-Collier
authors: Department of Translational Science & Molecular Medicine, Michigan State UniversityGrand Rapids, MI, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary'sGrand Rapids, MI, USA.
authors: Jack W
authors: JW
authors: Lipton
authors: Department of Translational Science & Molecular Medicine, Michigan State UniversityGrand Rapids, MI, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary'sGrand Rapids, MI, USA.
authors: Fredric P
authors: FP
authors: Manfredsson
keywords: Parkinson's disease; alpha-synuclein; dopamine; non-human primates; substantia nigra