Advances in Proteomics Allow Insights Into Neuronal Proteomes

Abstract

Protein–protein interaction networks and signaling complexes are essential for normal brain function and are often dysregulated in neurological disorders. Nevertheless, unraveling neuron- and synapse-specific proteins interaction networks has remained a technical challenge. New techniques, however, have allowed for high-resolution and high-throughput analyses, enabling quantification and characterization of various neuronal protein populations. Over the last decade, mass spectrometry (MS) has surfaced as the primary method for analyzing multiple protein samples in tandem, allowing for the precise quantification of proteomic data. Moreover, the development of sophisticated protein-labeling techniques has given MS a high temporal and spatial resolution, facilitating the analysis of various neuronal substructures, cell types, and subcellular compartments. Recent studies have leveraged these novel techniques to reveal the proteomic underpinnings of well-characterized neuronal processes, such as axon guidance, long-term potentiation, and homeostatic plasticity. Translational MS studies have facilitated a better understanding of complex neurological disorders, such as Alzheimer’s disease (AD), Schizophrenia (SCZ), and Autism Spectrum Disorder (ASD). Proteomic investigation of these diseases has not only given researchers new insight into disease mechanisms but has also been used to validate disease models and identify new targets for research.

Assessment of a 60-biomarker health surveillance panel (HSP) on whole blood from remote sampling devices by targeted LC/MRM-MS and discovery DIA-MS analysis

“…The biomarker panel could be expanded to include a broad range of low abundant organ specific protein signaling moieties circulating in the bloodstream. These organ derived moieties include myokines (skeletal muscle), 5,[61][62][63][64] osteokines (bone), 65,66 cardiokines (heart), 67 hepatokines (liver), 68,69 adipokines (white adipose tissue), 70 baptokines (brown adipose tissue) 71 and neurokines (neurons) [72][73][74] that may be monitored in health and disease, where intervention through exercise 43 can stimulate their release, promoting health in other tissues. 75,76 In addition, the protein activity/function in health and disease can be more specifically monitored through post-translational modifications (PTMs) such as phosphorylation, glycosylation and acetylation as well as monitoring single nucleotide polymorphisms (SNPs) by creating the representative SILs.…”

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins

“…Recent mass spectrometry-based proteomic studies identified activity-induced NSPs ( Alvarez-Castelao et al, 2017 ; Evans et al, 2020 ), including novel candidate plasticity proteins induced in response to visual experience ( Liu et al, 2018 ), indicating that proteomic approaches can reveal additional activity-responsive proteins and signaling pathways, commensurate with the complexity of the proteomic landscape ( Sharma et al, 2015 ; Fingleton et al, 2021 ). Labeling NSPs through the incorporation of azide-containing noncanonical amino acid (ncAA) methionine analogs combined with click chemistry conjugation to alkynes, also known as bio-orthogonal ncAA tagging (BONCAT; Dieterich et al, 2006 ), has been an important approach to study protein dynamics ( Howden et al, 2013 ; Saleh et al, 2019 ).…”

Cell-type-specific neuroproteomics of synapses

“…Bio-orthogonal non-canonical amino acid tagging (BONCAT) is a metabolic label that enriches cell-specific proteomes. A mutant methionyl-tRNA synthetase (MetRS L274G ) labels newly translated proteins with the non-canonical amino acid [111]. This tool is very powerful in labeling newly synthesized proteins in a cell-type-specific manner when applied with Cre-loxP transgenic animals.…”