title: Presynaptic alpha-synuclein aggregation in a mouse model of Parkinson's disease.
abstract: Parkinson's disease and dementia with Lewy bodies are associated with abnormal neuronal aggregation of α-synuclein. However, the mechanisms of aggregation and their relationship to disease are poorly understood. We developed an in vivo multiphoton imaging paradigm to study α-synuclein aggregation in mouse cortex with subcellular resolution. We used a green fluorescent protein-tagged human α-synuclein mouse line that has moderate overexpression levels mimicking human disease. Fluorescence recovery after photobleaching (FRAP) of labeled protein demonstrated that somatic α-synuclein existed primarily in an unbound, soluble pool. In contrast, α-synuclein in presynaptic terminals was in at least three different pools: (1) as unbound, soluble protein; (2) bound to presynaptic vesicles; and (3) as microaggregates. Serial imaging of microaggregates over 1 week demonstrated a heterogeneous population with differing α-synuclein exchange rates. The microaggregate species were resistant to proteinase K, phosphorylated at serine-129, oxidized, and associated with a decrease in the presynaptic vesicle protein synapsin and glutamate immunogold labeling. Multiphoton FRAP provided the specific binding constants for α-synuclein's binding to synaptic vesicles and its effective diffusion coefficient in the soma and axon, setting the stage for future studies targeting synuclein modifications and their effects. Our in vivo results suggest that, under moderate overexpression conditions, α-synuclein aggregates are selectively found in presynaptic terminals.
authors: Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, Oregon 97239, Research Services, Neurocytology Laboratory, Veterans Affairs Medical Center, Portland, Oregon 97239, Departments of Behavioral Neuroscience and Pathology, Oregon Health and Science University, Portland, Oregon 97239, and Parkinson Center of Oregon, Department of Neurology, Oregon Health and Science University, Portland, Oregon 97239.
authors: Kateri J
authors: KJ
authors: Spinelli
authors: Jonathan K
authors: JK
authors: Taylor
authors: Valerie R
authors: VR
authors: Osterberg
authors: Madeline J
authors: MJ
authors: Churchill
authors: Eden
authors: E
authors: Pollock
authors: Cynthia
authors: C
authors: Moore
authors: Charles K
authors: CK
authors: Meshul
authors: Vivek K
authors: VK
authors: Unni
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D036681:Fluorescence Recovery After Photobleaching / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D051844:alpha-Synuclein / Q000032:analysis / Q000096:biosynthesis*
chemical_list: D051844:alpha-Synuclein