Abstract
The mammalian nervous system is an immensely heterogeneous organ composed of a diverse collection of neuronal types that interconnect in complex patterns. Synapses are highly specialized neuronal cell-cell junctions with common and distinct functional characteristics that are governed by their protein composition or synaptic proteomes. Even a single neuron can possess a wide-range of different synapse types and each synapse contains hundreds or even thousands of proteins. Many neurological disorders and diseases are caused by synaptic dysfunction within discrete neuronal populations. Mass spectrometry (MS)-based proteomic analysis has emerged as a powerful strategy to characterize synaptic proteomes and potentially identify disease driving synaptic alterations. However, most traditional synaptic proteomic analyses have been limited by molecular averaging of proteins from multiple types of neurons and synapses. Recently, several new strategies have emerged to tackle the ‘averaging problem’. In this review, we summarize recent advancements in our ability to characterize neuron-type specific and synapse-type specific proteomes and discuss strengths and limitations of these emerging analysis strategies.
Highlights
The mammalian nervous system is a complex organ assembled from millions of neurons in complex circuits arranged into elaborate networks
The recent development of highly sensitive and robust RNA sequencing (RNA-Seq) technologies has led to a boom in single cell analyses and significantly increased our understanding of global gene expression patterns of discrete neuronal populations in healthy and stressed conditions [53,54,55]
mass spectrometry (MS)-based strategies are beginning to bridge this gap, and over the coming years, we will eventually reach a deep understanding of neuron-type and synapse-type specific proteomes
Summary
The mammalian nervous system is a complex organ assembled from millions of neurons in complex circuits arranged into elaborate networks. Neurons, synapses, and synaptic proteins are impaired in Alzheimer’s disease (AD) [12,13]. A deep understanding of the mechanisms and proteins regulating discrete synapses formed locally or between long-range axonal projections and their postsynaptic counterparts is a key step towards developing effective treatments for a wide range of neurological disorders. Determining the proteins and molecular mechanisms responsible for altered circuit function of specific neurons and discrete synapses in discovery-mode, represents an important opportunity that is only becoming achievable [18]. The hope is that by identifying small groups of altered proteins in specific neurons and synapses, we will be able to advance our understanding of synaptic dysfunction and discover new therapeutic targets
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