ABSTRACT
The effects of psychedelics encompass modulation of subjective experience, neuronal plasticity, brain activity and connectivity, constituting a complex phenomenon. Underlying these effects, molecular changes at the protein level are expected. Proteomic analysis of human brain cells can elicit a comprehensive view of proteins and biological processes regulated within the central nervous system. To explore the molecular pathways influenced by lysergic acid diethylamide (LSD), we utilized mass spectrometry-based proteomics on human brain organoids. This approach allowed for an in-depth analysis of the proteomic alterations induced by LSD, providing insights into its effects at the molecular level within a brain-like environment. Alterations in proteostasis and energy metabolism, which are required for neural plasticity, were observed. Alongside, we identified changes in protein synthesis, folding, autophagy, and proteasomal degradation, as well as in glycolysis, oxidative phosphorylation, cytoskeleton regulation, and neurotransmitter release, providing a comprehensive view of the regulation of cellular process by LSD exposure. Furthermore, the ability of LSD to induce plasticity in human brain cells was corroborated through complementary in vitro experiments focusing on neurite outgrowth. This study sheds light on the specific proteins that LSD influences, thereby enhancing neurite extension and plasticity.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Correction of the color pattern of the figures.
ABBREVIATIONS
- α-SNAP
- soluble NSF attachment protein α
- 5-HT
- 5-hydroxytryptamine
- ACTN
- actinin
- AP2
- adaptor protein 2 complex
- ATP
- adenosine triphosphate
- BDNF
- brain-derived neurotrophic factor
- BSA
- bicinchoninic acid
- BSA
- bovine serum albumin
- cDNA
- Complementary DNA
- CME
- clathrin-mediated endocytosis
- CNS
- central nervous system
- CPNE1
- copine-1
- DAP
- differentially abundant proteins
- DAPI
- 4’ 6-Diamidino-2-Phenylindole
- DAVID
- Database for Annotation, Visualization, and Integrated Discovery
- DIA
- data-independent acquisition
- DMEM/F12
- Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12
- DNA
- deoxyribonucleic acid
- DTT
- dithiothreitol
- ERM
- ezrin, radixin or moesin
- F2
- coagulation factor II
- F2R
- coagulation factor II receptor
- FC
- fold change
- FDR
- false discovery rate
- fMRI
- functional magnetic resonance imaging
- FN1
- fibronectin 1
- Gα12,13
- G protein subunit alpha 12, 13
- GABA
- gamma- aminobutyric acid
- GF
- growth factor
- GPCR
- G protein-coupled receptor
- GTPase
- guanosine triphosphatases
- Glu-Fib
- [Glu1]-fibrinopeptide B human
- HDMSE
- high-definition data-independent mass spectrometry
- hESC
- human embryonic stem cell
- HGNC
- HUGO Gene Nomenclature Committee
- hiPSC
- human induced pluripotent stem cell
- HUGO
- Human Genome Organization
- ITG
- integrin
- KEGG
- Kyoto Encyclopedia of Genes and Genomes
- KSR
- KnockOut Serum Replacement
- LC-MS/MS
- liquid chromatography tandem mass spectrometry
- LSD
- lysergic acid diethylamide
- M-MLV
- moloney murine leukemia virus
- MAP2
- microtubule-associated protein 2
- MCODE
- Molecular Complex Detection
- MEM-NEAA
- minimum essential media-nonessential amino acids
- MLC
- myosin light chain
- mRNA
- messenger ribonucleic acid
- mTOR
- mammalian target of rapamycin
- mTeSR1
- modified TeSR1 medium
- NADH
- nicotinamide adenine dinucleotide
- NSF
- N-ethylmaleimide-sensitive fusion protein
- NSC
- neural stem cell
- NT
- neurotransmitter
- OGA
- O-GlcNAcase
- PBS
- phosphate-buffered saline
- PCR
- polymerase chain reaction
- PFA
- paraformaldehyde
- Pen-Strep
- Penicillin-Streptomycin
- PPI
- protein-protein interaction
- Rho
- Rat sarcoma virus homolog
- ROCK
- Rho kinase
- ROCKi
- Rho- associated protein kinase inhibitor
- RIM
- Rab-interacting molecule
- RNA
- ribonucleic acid
- SNAP
- soluble NSF attachment proteins
- SNARE
- soluble NSF adaptor protein receptor
- RPM
- rotation per minute
- RTK
- Receptor Tyrosine Kinase
- STRING
- Search Tool for the Retrieval of Interacting Genes
- t-SNARE
- target SNARE
- TCA
- tricarboxylic acid
- Taq
- Thermus aquaticus
- TeSR1
- serum-free medium for human pluripotent stem cells
- TrkB
- tropomyosin receptor kinase B
- VAMP
- vesicle-associated membrane protein
- VGCC
- voltage-gated calcium channel
- V-ATPase
- vacuolar ATPase
- v-SNARE
- vesicle SNARE
