Neurotransmitter alterations in metabolic and psychiatric disorders
Neurotransmitters are signal molecules that nerve cells use to communicate. The neurotransmitters dopamine and norepinephrine work as neuromodulators and adjust the communication strength between neurons. In this way, they help control many different brain activities, such as movement, attention, memory, learning, stress and addiction and they are implicated in many neurological and psychiatric disorders.
ADHD-like symptoms in metabolic disease
Dopamine and norepinephrine are made from the amino acid tyrosine, through several chemical reactions, where the first step is catalyzed by the enzyme tyrosine hydroxylase (abbreviated as TH). The brain rely on supply of tyrosine from the blood and this may be affected by metabolic diseases. Patients with hereditary tyrosinemia type 1 have deficient function of a liver enzyme in the metabolization of tyrosine and develop severe liver problems and early death if not treated with nitisinone. This treatment leads to very high plasma levels of tyrosine. We recently studied the possible impact of these high tyrosine levels on cognitive functions and on the activity of TH and the sister enzyme tryptophan hydroxylase (TPH), important for serotonin synthesis . We found clear positive correlation between the plasma levels of tyrosine and inattention symptoms, which may suggest too little dopamine synthesis. This apparent paradox could be related to the strong substrate inhibition observed for TH and inhibition of TPH by the high tyrosine levels.
Dial 14-3-3 for control
The reaction catalyzed by TH is an important checkpoint for regulating the level of dopamine and norepinephrine. TH is regulated by several cell signaling pathways that turn on and off various "switches" on the enzyme, e.g. by chemical modifications such as phosphorylation. This changes the properties and efficiency of TH. In a recent publication we have studied how multiple signaling pathways can communicate through protein-protein interactions . The 14-3-3 proteins are abundant proteins in the brain that are found to regulate many different neuronal processes. The 14-3-3s are also binding partners of TH that regulate its activity. We have now found that this interaction can also directly influence the on and off modification processes that target different regulatory sites on TH. The 14-3-3 proteins can thereby control the length and timing of signals that regulate TH activity.
The 14-3-3 proteins have been implicated in several neuropsychiatric disorders. Our collaborators at the University of Barcelona have just now described the implications of mutations in 14-3-3 genes in autism spectrum disorder and schizophrenia . In particular, a mutation in one of the 14-3-3 genes accumulated in a family with autism and functional studies performed by researchers in MEDIATE found severe effects on the solubility of the protein and its ability to bind the target protein TH.
For more details:
 Barone, H. et al. (2020) Tyrosinemia Type 1 and symptoms of ADHD: Biochemical mechanisms and implications for treatment and prognosis. https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.b.32764
 Ghorbani, S. et al. (2020) Serine 19 phosphorylation and 14‐3‐3 binding regulate phosphorylation and dephosphorylation of tyrosine hydroxylase on serine 31 and serine 40. https://onlinelibrary.wiley.com/doi/full/10.1111/jnc.14872
 Torrico, B. et al. (2020) Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses. https://www.mdpi.com/2077-0383/9/6/1851