Novel Schizophrenia Biomarker and Potential Therapeutic Strategy Identified

Current schizophrenia (SZ) medications treat symptoms such as hallucinations and delusions, but do little for cognitive symptoms, such as disorganized thinking or executive dysfunction. As a result, many patients are unable to work, rely on family for lifelong support, become homeless or, in some cases, experience suicidal thoughts and actions.

A study in humans and mice, headed by a team at Northwestern University, has discovered a novel biomarker of schizophrenia that could also serve as a new drug candidate to treat cognitive symptoms of the disorder. Their research in a mouse model of schizophrenia showed that treatment with a synthetic protein, SEAD1, corrected overexcited brain circuits. “A lot of people with schizophrenia cannot integrate well into society because of these cognitive deficits,” said Peter Penzes, PhD, professor of neuroscience, pharmacology and psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine. “Our discovery could solve these challenges by establishing the basis of a revolutionary and completely novel treatment strategy through a tandem biomarker-peptide therapeutic approach.”

Penzes, who is also is the director of the Center for Autism and Neurodevelopment at Feinberg, is corresponding author of the team’s published paper in Neuron, titled “Soluble α2δ-1, altered in disease CSF, modulates network homeostasis and rescues deficits in a neuropsychiatric mouse model.” In their paper the team reported “Unlike dopamine-targeting antipsychotics, which primarily address positive symptoms but offer limited improvement for cognitive or negative symptoms, SEAD1 directly modulates cortical networks implicated in these unmet domains.”

Cognitive deficits remain what the authors term “one of the unmet therapeutic needs in schizophrenia.” Among the different factors that have been implicated in the disorder, “… synaptic abnormalities in excitatory and inhibitory (E/I) neurons are proposed as key mechanisms underlying cognitive dysfunction,” they wrote. Numerous risk genes for psychiatric disorders encode synaptic proteins, and many of these are membrane bound, the team continued. “Some membrane proteins undergo ectodomain shedding, in which proteases, called sheddases, cleave the protein to release a soluble extracellular protein fragment that can have transcellular signaling properties.” The authors asked whether soluble ectodomains derived from synaptic membrane proteins might be altered in the CSF of individuals with SZ compared.

By examining the cerebral spinal fluid of more than 100 schizophrenia patients and healthy controls, the scientists identified a previously unknown, soluble, freely circulating form of a protein α2δ-1—a calcium channel auxiliary subunit—which is encoded by the CACNA2D1 gene. The team found that in patients with schizophrenia, levels of this protein signal are reduced compared to controls, which results in overactive or overexcited brain circuits.

The team created a synthetic version of the protein, SEAD1 (synthetic ectodomain of Alpha2Delta-1) and tested it in a mouse model of genetic schizophrenia. The results showed that a single injection of SEAD1 into the animals’ brains corrected both the abnormal brain circuit activity and the behavioral deficits, including memory and social problems. “A single SEAD1 injection into the prefrontal cortex of a genetic mouse model of SZ reversed synaptic and behavioral deficits, including memory and social impairments,” they reported. “In conclusion, soluble α2δ-1 is a previously unrecognized extracellular regulator of cortical E/I balance that links molecular synaptic mechanisms with network function and behavior … SEAD1 appears to act on disease-altered circuits, normalizing prefrontal E/I balance by selectively enhancing inhibitory neuron function.” Importantly, the treatment did not cause observable negative side effects, such as sedation or reduced movement.

“Our treatment reopens a crucial window to rewire connections in adult brains,” said first author Marc Dos Santos, PhD, a research assistant professor of neuroscience at Feinberg. “The lack of brain plasticity is believed to be a key factor in the development of symptoms in schizophrenia. Reforming synapses could also be beneficial for other mental disorders, such as depression.”

Dos Santos said the team does not yet know how long the therapeutic effects last, but they plan to study this aspect in future experiments. The research team is now optimizing this protein for future clinical trials in patients with 16p11.2 duplication syndrome, which is associated with a tenfold risk of developing schizophrenia, Penzes said.

While there are biomarkers to diagnose diseases—such as blood sugar for diabetes or cholesterol for heart disease—diagnosing psychiatric disorders is much more subjective, Penzes further commented. Additionally, many potential drugs don’t perform well in clinical trials or later fail because of the diversity of people’s biology. By identifying a specific schizophrenia biomarker in this study, the scientists can now identify a subgroup of people who would most likely respond well to this SEAD1-based peptide drug.

The biomarker-therapeutic combination is revolutionary because it uses the biomarker to identify patients most likely to benefit from this treatment and uses the biomarker-related peptide drug to treat those same patients. “This work underscores the translational value of CSF proteomics for identifying circuit-relevant biomarkers and guiding the development of circuit-modulating therapeutics,” the authors wrote in conclusion. Reduced soluble α2δ-1 in SZ CSF suggests its utility as both a therapeutic target and a stratification biomarker for precision intervention.”

Penzes stated, “The clinical trials would have much higher success rate, and the treatments would work much better because you would give the new drug to the exact people who actually could respond to that drug … The next step for us would be to develop a blood biomarker to identify a subset of schizophrenia patients who can respond to this treatment, and then we can give them this peptide—almost like Ozempic for schizophrenia, an injection that you can give once a week.”

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