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From gene to protein

Each protein is a chain of amino acids linked in sequence, like beads on a necklace. There are 20 standard amino acids, and their order is set by the corresponding gene in DNA. First the gene is copied into messenger RNA; then ribosomes read that RNA and join the amino acids one by one.

A typical protein has hundreds of amino acids. Since each position can hold one of 20 types, the number of possible sequences is astronomical — and that variety is what lets proteins carry out such different jobs.

Shape defines function

Right after it is made, the chain folds into a specific three-dimensional shape. Folding is guided by the chemistry of the amino acids: hydrophobic ones (which “avoid” water) tend to end up inside, while polar and charged ones face the watery environment of the cell.

Proteins in the brain

A protein can also receive chemical “tags” after it is made — post-translational modifications such as phosphorylation. They switch the protein on, off or redirect it, acting as fine switches of cell function.

Genome × proteome

The genome — the full set of genes — is virtually the same in every cell of the body. The proteome, the set of proteins present, changes with cell type, brain region, age, medication and health. That makes the proteome a much closer portrait of what the cell is actually doing.

There is an extra layer of complexity: the roughly 20,000 human protein-coding genes give rise to many more distinct protein forms (proteoforms), thanks to alternative RNA processing and post-translational modifications.

How an experiment works

Quantifying to compare

Identifying proteins is only half the job. The scientific question is usually comparative: which proteins are more or less abundant in tissue from people with schizophrenia compared with controls? What changes in cells treated with an antidepressant? For that, quantification strategies — with or without chemical labeling of samples — and rigorous statistics are used.

Neurons and glia

The human brain has, on average, about 86 billion neurons — a figure estimated by Brazilian researchers — and a similar number of glial cells. Neurons receive signals through dendrites, integrate them in the cell body and send electrical impulses along the axon to the terminals, where they communicate with other cells.

The chemical synapse

When the impulse reaches the axon terminal, vesicles release neurotransmitters into a tiny gap, the synaptic cleft. These molecules bind to receptors — proteins — on the next cell's membrane, opening channels or triggering signaling cascades. Then transporters take the neurotransmitter back up (reuptake) or enzymes break it down, ending the signal.

Myelin: the neurons' insulating tape

Myelin wraps axons in layers, like insulating tape. Impulses “jump” between small unmyelinated gaps, the nodes of Ranvier, exceeding 100 meters per second in the fastest fibers. When myelin or oligodendrocytes change, communication between distant brain regions can become slower and less synchronized.

According to the World Health Organization, schizophrenia affects about 24 million people worldwide — roughly 1 in 300. Symptoms usually emerge in late adolescence or early adulthood, generally somewhat earlier in men.

Three groups of symptoms

What science already knows

Schizophrenia is multifactorial: there is an important genetic component, made of many small-effect variants, that interacts with environmental factors such as pregnancy and birth complications, stress and cannabis use in adolescence.

The proteomics perspective

By comparing the proteome of brain tissue donated by people with and without schizophrenia, proteomic studies have found recurring changes in proteins linked to oligodendrocytes and myelin, to cellular energy metabolism and to synapse structure. Cell models make it possible to test whether these changes are cause or consequence — and how medications modify them.

The WHO estimates that around 280 million people live with depression — about 5% of adults — and it is more common in women. It is one of the leading causes of disability worldwide.

Diagnosis is clinical and considers symptoms lasting at least two weeks: depressed mood, loss of interest or pleasure (anhedonia), changes in sleep and appetite, fatigue, trouble concentrating, feelings of guilt and, in severe cases, thoughts of death.

From monoamines to plasticity

In the 1950s, some drugs were observed to change mood by altering levels of serotonin, noradrenaline and dopamine — the monoamines. That gave rise to the monoamine hypothesis. But there is a puzzle: antidepressants raise monoamines within hours, while improvement takes weeks. This suggests the effect depends on slower adaptations in the brain.

Why doesn't everyone respond to treatment?

Psychotherapy and antidepressants work for many people, but a significant share — estimated at around 30% — does not respond well to initial treatments. Understanding, at the protein level, how each drug works and what distinguishes responders from non-responders is one path toward more personalized treatment. Newer approaches such as esketamine, which acts on the glutamate system, reinforce that more than one biological pathway is involved.

The search for biomarkers

A biomarker is a measurable feature that signals a biological process — like blood glucose in diabetes. In psychiatry, diagnosis still relies almost entirely on clinical assessment. Proteins measured in blood or other fluids could help diagnose earlier, predict response to a drug or track treatment progress.

Models to study the brain

By combining these models with proteomics, we can ask how an altered protein affects the cell, test drug candidates and, in the future, choose the most suitable treatment for each person — so-called precision medicine.