title: Sorting out release, uptake and processing of alpha-synuclein during prion-like spread of pathology.
abstract: Parkinson's disease is a progressive neurological disorder that is characterized by the formation of intracellular protein inclusion bodies composed primarily of a misfolded and aggregated form of the protein α-synuclein. There is growing evidence that supports the prion-like hypothesis of α-synuclein progression. This hypothesis postulates that α-synuclein is a prion-like pathological agent and is responsible for the progression of Parkinson pathology in the brain. Potential misfolding or aggregation of α-synuclein that might occur in the peripheral nervous system as a result of some insult, environmental or genetic (or more likely a combination of both) that might spread into the midbrain, eventually causing degeneration of the neurons in the substantia nigra. As the disease progresses further, it is likely that α-synuclein pathology continues to spread throughout the brain, including the cortex, leading to deterioration of cognition and higher brain functions. While it is unknown why α-synuclein initially misfolds and aggregates, a great deal has been learned about how the cell handles aberrant α-synuclein assemblies. In this review, we focus on these mechanisms and discuss them in an attempt to define the role that they might play in the propagation of misfolded α-synuclein from cell-to-cell. The prion-like hypothesis of α-synuclein pathology suggests a method for the transmission of misfolded α-synuclein from one neuron to another. This hypothesis postulates that misfolded α-synuclein becomes aggregation prone and when released and taken up by neighboring cells, seeds further misfolding and aggregation. In this review we examine the cellular mechanisms that are involved in the processing of α-synuclein and how these may contribute to the prion-like propagation of α-synuclein pathology. This article is part of a special issue on Parkinson disease.
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Tyson
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Steiner
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA. patrik.brundin@vai.org.
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
mesh_terms: D000818:Animals; D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology; D000072002:Prion Proteins / Q000096:biosynthesis* / Q000378:metabolism*; D066329:Protein Aggregates / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000378:metabolism*
chemical_list: D000072002:Prion Proteins; D066329:Protein Aggregates; D051844:alpha-Synuclein
keywords: Parkinson's disease; autophagy; exocytosis; homeostasis; prion; α-synuclein