Abstract
α-Synuclein is a presynaptic protein that regulates synaptic vesicle trafficking under physiological conditions. However, in several neurodegenerative diseases, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, α-synuclein accumulates throughout the neuron, including at synapses, leading to altered synaptic function, neurotoxicity, and motor, cognitive, and autonomic dysfunction. Neurons typically contain both monomeric and multimeric forms of α-synuclein, and it is generally accepted that disrupting the balance between them promotes aggregation and neurotoxicity. However, it remains unclear how distinct molecular species of α-synuclein affect synapses where α-synuclein is normally expressed. Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric α-synuclein impaired distinct stages of clathrin-mediated synaptic vesicle endocytosis, leading to a loss of synaptic vesicles. Here, we expand this knowledge by investigating the effects of native, physiological α-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically folded multimeric α-synuclein with a minor component of monomeric α-synuclein. After acute introduction of excess brain-derived human α-synuclein, there was a moderate reduction in the synaptic vesicle cluster and an increase in the number of large, atypical vesicles called “cisternae.” In addition, brain-derived α-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone. In contrast to monomeric or dimeric α-synuclein, the brain-derived multimeric α-synuclein did not appear to alter clathrin-mediated synaptic vesicle endocytosis. Taken together, these data suggest that excess brain-derived human α-synuclein impairs intracellular vesicle trafficking and further corroborate the idea that different molecular species of α-synuclein produce distinct trafficking defects at synapses. These findings provide insights into the mechanisms by which excess α-synuclein contributes to synaptic deficits and disease phenotypes.
Highlights
Synucleinopathies, including Parkinson’s disease, dementia with Lewy Bodies (DLB) and multiple system atrophy, are neurodegenerative diseases that are pathologically characterized by the abnormal accumulation and aggregation of α-synuclein within neuronal cell bodies and neurites (Spillantini and Goedert, 2000; Henderson et al, 2019; Sulzer and Edwards, 2019; Brás et al, 2020)
Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric α-synuclein impaired distinct stages of clathrin-mediated synaptic vesicle endocytosis, leading to a loss of synaptic vesicles
The plasma membrane evaginations and clathrin-coated intermediates were relatively normal (Figure 3). These data indicate that clathrin-mediated synaptic vesicle endocytosis from the plasma membrane was relatively unaffected after introduction of excess brainderived human α-synuclein and suggest that instead there was a moderate impairment of intracellular vesicle trafficking (Figure 8)
Summary
Synucleinopathies, including Parkinson’s disease, dementia with Lewy Bodies (DLB) and multiple system atrophy, are neurodegenerative diseases that are pathologically characterized by the abnormal accumulation and aggregation of α-synuclein within neuronal cell bodies and neurites (Spillantini and Goedert, 2000; Henderson et al, 2019; Sulzer and Edwards, 2019; Brás et al, 2020). Synaptic accumulation of α-synuclein may be an early pathological event in synucleinopathies, leading to disruptions of axonal endosomal trafficking, as well as synaptic dysfunction (Nemani et al, 2010; Scott et al, 2010; Boassa et al, 2013; Eisbach and Outeiro, 2013; Spinelli et al, 2014; VolpicelliDaley et al, 2014; Hunn et al, 2015). Synaptic aggregation of α-synuclein is highly correlated with cognitive deficits and dementia in DLB patients (Kramer and SchulzSchaeffer, 2007; Schulz-Schaeffer, 2010). These observations highlight the importance of understanding the direct effects of excess α-synuclein at synapses
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