Hyperprolinemia has been shown to correlate with the risk of psychosis, schizophrenia, schizoaffective disorder, and seizures in a number of human diseases. One cause of hyperprolinemia is loss-of-function mutations of the PRODH gene, which is involved in L-proline degradation. The PRODH gene maps in the 22q11.2 locus, and is heterozygously deleted in the 22q11.2 microdeletion syndrome, which is associated with high-risk for neurodevelopmental abnormalities and psychosis. One hypothesis explaining the effects of elevated L-proline within the CNS is that L-proline may act as a neuroactive small molecule that interferes with the normal function of other neurotransmitter systems within the brain. In preliminary studies we have found that L-proline is a GABA-mimetic metabolite capable of activating GABA-A receptor ion channels. Based on chemical structural database searches we have identified two additional "proline-like" metabolites that are known to accumulate in two other human neuropsychiatric diseases: -aminolevulinic acid, which accumulates in acute intermittent porphyria, a disease associated with psychosis and seizures, and L-pipecolic acid, which accumulates in pyridoxine (vitamin B6) dependent epilepsy, a disease associated with seizures. Similar to L-proline, we have found that both of these metabolites are also GABA-mimetic and capable of activating GABA-A receptors. We hypothesize that accumulation of these GABA-mimetic metabolites within the CNS may disrupt normal GABA-ergic synaptic transmission in these diseases with overlapping neuropsychiatric symptomatology. To test this hypothesis we have proposed the following Specific Aims: (1) to determine whether these metabolites interfere with normal GABA processing, handling, and detection by the components of the GABA-system and (2) to determine the impact of L-proline accumulation upon GABA-ergic synaptic transmission and network properties within the medial prefrontal cortex. The results of our proposed studies will provide important initial insights into the role of accumulated metabolites in GABA-ergic dysfunction in these clinically relevant human diseases with overlapping neurodevelopmental and neuropsychiatric dysfunction. These results will also lay the foundation for guiding future studies targeted at the development of pharmacological rescue strategies for these diseases.
A number of neuropsychiatric phenotypes as well as seizure disorders have been linked to increased proline in the brain. Based on chemical structural database searches, we have formulated a hypothesis that this link may be due to proline having a structure similar to endogenous neurotransmitters in the brain (specifically GABA), thus interfering with their function. We propose a series of experiments to test this hypothesis, extend it to other similar metabolites and provide mechanistic insights for future drug development efforts.
|Crabtree, Gregg W; Park, Alan J; Gordon, Joshua A et al. (2016) Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade. Cell Rep 17:570-582|