Determining if mitochondrial complex I underlies neural dysfunction in schizophrenia
Lead Research Organisation:
KING'S COLLEGE LONDON
Abstract
The challenge: Schizophrenia is a top cause of global disability and costs are ~100 billion Euros per year in Europe alone. Cognitive impairment is a leading contributor to the disability of the disorder, and there is no licensed drug treatment for it. Consequently, cognitive impairment is a major unmet need in schizophrenia. Moreover, focus groups involving people with schizophrenia and carers were unanimous that identifying treatment targets for cognitive impairment is a top priority.
Aim: to test a mechanism thought to underlie cognitive impairment in schizophrenia and validate a potential biological target for treatment.
Context: Brain cells have high energy needs. The first step in cellular energy production requires mitochondrial protein complex 1 (MC1) to catalyse electron transfer from NADH (producing NAD+), which is required for ATP synthesis. Multiple lines of genetic, cellular and post-mortem evidence indicate that schizophrenia is associated with impaired MC1 levels and function. In vivo brain imaging data show that people with schizophrenia have lower NAD+/NADH ratios and less MC1 in the frontal part of their brains than healthy people, and that lower MC1 levels are related to lower brain activity during cognitive tasks and poorer cognitive function. These data indicate that lower MC1 levels in schizophrenia could impair brain function to underlie cognitive impairments in the disorder.
Our proposed project will provide a crucial test of this mechanism. Our hypothesis is that bypassing MC1 will increase NAD+/NADH ratios and restore brain activity in schizophrenia. We will use methylene blue as a mechanistic probe. This drug transfers electrons from NADH to the next step in ATP synthesis, bypassing MC1. If our hypothesis is correct, administering this drug will increase NAD+/NADH ratios and neural activity and so improve cognitive function in schizophrenia. We will test the effect of methylene blue on NAD+/NADH and brain activity using magnetic resonance imaging measures of brain activity and cognitive performance during a cognitive task in people with schizophrenia.
Timeliness: the new lines of genetic, cellular and PET evidence for MC1 alterations in schizophrenia mean it is timely to test this target. Moreover, a number of pharmaceutical companies are developing drugs that could target MC1.
Applications and benefits: The findings will benefit researchers in the field by providing a key test of whether MC1 dysfunction underlies altered neural activity in schizophrenia and could result in a paradigm shift in the understanding of schizophrenia by providing the first in vivo evidence of a molecular mechanism underlying cognitive impairments. Findings will also be relevant to other disorders where MC1 has been implicated (e.g. Alzheimer’s disease, bipolar disorder)
Impact: the study could identify MC1 as a treatment target with the potential to lead to the first medicine for a major unmet need in schizophrenia, benefiting people with schizophrenia, healthcare systems and society in general. It could also inform the development of treatments targeting this approach for other disorders with cognitive impairments.
Aim: to test a mechanism thought to underlie cognitive impairment in schizophrenia and validate a potential biological target for treatment.
Context: Brain cells have high energy needs. The first step in cellular energy production requires mitochondrial protein complex 1 (MC1) to catalyse electron transfer from NADH (producing NAD+), which is required for ATP synthesis. Multiple lines of genetic, cellular and post-mortem evidence indicate that schizophrenia is associated with impaired MC1 levels and function. In vivo brain imaging data show that people with schizophrenia have lower NAD+/NADH ratios and less MC1 in the frontal part of their brains than healthy people, and that lower MC1 levels are related to lower brain activity during cognitive tasks and poorer cognitive function. These data indicate that lower MC1 levels in schizophrenia could impair brain function to underlie cognitive impairments in the disorder.
Our proposed project will provide a crucial test of this mechanism. Our hypothesis is that bypassing MC1 will increase NAD+/NADH ratios and restore brain activity in schizophrenia. We will use methylene blue as a mechanistic probe. This drug transfers electrons from NADH to the next step in ATP synthesis, bypassing MC1. If our hypothesis is correct, administering this drug will increase NAD+/NADH ratios and neural activity and so improve cognitive function in schizophrenia. We will test the effect of methylene blue on NAD+/NADH and brain activity using magnetic resonance imaging measures of brain activity and cognitive performance during a cognitive task in people with schizophrenia.
Timeliness: the new lines of genetic, cellular and PET evidence for MC1 alterations in schizophrenia mean it is timely to test this target. Moreover, a number of pharmaceutical companies are developing drugs that could target MC1.
Applications and benefits: The findings will benefit researchers in the field by providing a key test of whether MC1 dysfunction underlies altered neural activity in schizophrenia and could result in a paradigm shift in the understanding of schizophrenia by providing the first in vivo evidence of a molecular mechanism underlying cognitive impairments. Findings will also be relevant to other disorders where MC1 has been implicated (e.g. Alzheimer’s disease, bipolar disorder)
Impact: the study could identify MC1 as a treatment target with the potential to lead to the first medicine for a major unmet need in schizophrenia, benefiting people with schizophrenia, healthcare systems and society in general. It could also inform the development of treatments targeting this approach for other disorders with cognitive impairments.