Abstract
Alpha-synuclein is a predominant player in the pathogenesis of Parkinson's Disease. However, despite extensive study for two decades, its physiological and pathological mechanisms remain poorly understood. Alpha-synuclein forms a perplexing web of interactions with lipids, trafficking machinery, and other regulatory factors. One emerging consensus is that synaptic vesicles are likely the functional site for alpha-synuclein, where it appears to facilitate vesicle docking and fusion. On the other hand, the dysfunctions of alpha-synuclein are more dispersed and numerous; when mutated or over-expressed, alpha-synuclein affects several membrane trafficking and stress pathways, including exocytosis, ER-to-Golgi transport, ER stress, Golgi homeostasis, endocytosis, autophagy, oxidative stress, and others. Here we examine recent developments in alpha-synuclein's toxicity in the early secretory pathway placed in the context of emerging themes from other affected pathways to help illuminate its underlying pathogenic mechanisms in neurodegeneration.
Highlights
Alpha-synuclein (a-syn), a 14 kD cytosolic neuronal protein, has been a major focus of Parkinson’s Disease (PD) pathological studies
The neuronal toxicity of alpha-synuclein over-expression or mutation appears to involve a wide range of pathways and cellular functions including ER-to-Golgi transport, Golgi homeostasis, presynaptic trafficking, endocytosis, autophagy, the ubiquitinproteasome system, ER and oxidative stress (Snead and Eliezer, 2014)
There could be more fundamental link(s) whereby the ubiquitin-proteasome system (UPS) promotes ER homeostasis, for example through a direct regulatory role in the initiation of unfolded protein response (UPR), ER associated degradation (ERAD), or ER-phagy. This could help explain why multiple neurodegenerative diseases involving aggregated cytosolic proteins result in UPR–a process conventionally viewed as initiated in the ER lumen
Summary
Alpha-synuclein (a-syn), a 14 kD cytosolic neuronal protein, has been a major focus of Parkinson’s Disease (PD) pathological studies. The neuronal toxicity of alpha-synuclein over-expression or mutation appears to involve a wide range of pathways and cellular functions including ER-to-Golgi transport, Golgi homeostasis, presynaptic trafficking, endocytosis, autophagy, the ubiquitinproteasome system, ER and oxidative stress (Snead and Eliezer, 2014). Alpha-syn synaptic function vs dysfunction is likely very sensitive to concentration and the aggregation state of a-syn species, keeping in mind that conversion to pathogenic forms will deplete cells of the functional form.
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