Parkinsonian phenotypes induced by Synphilin-1 expression are differentially contributed by serotonergic and dopaminergic circuits and suppressed by nicotine treatment.

Synphilin-1 is a protein encoded by the human SNCAIP gene whose function has yet to be fully understood. However, it has been linked to familial Parkinson's disease (PD). Synphilin-1 is a major component of the Lewy bodies found in neurons in the substantia nigra pars compacta of PD patients. Synphilin-1 expression in serotonergic and/or dopaminergic neurons of Drosophila melanogaster induces neurodegeneration, as well as motor and non-motor PD like symptoms. In this work, we examined the contribution of the serotonergic and dopaminergic circuits in the development of PD-like phenotypes. We found that olfactory and visual symptoms are majorly contributed by the serotonergic system, and that motor symptoms and reduction in survival are mainly contributed by the dopaminergic system. Chronic nicotine treatment was able to suppress several of these symptoms. These results indicate that both the serotonergic and dopaminergic systems contribute to different aspects of PD symptomatology and that nicotine has beneficial effects on specific symptoms.

The BE (2)-M17 cell line has a better dopaminergic phenotype than the traditionally used for Parkinson´s research SH-SY5Y, which is mostly serotonergic.

SH-SY5Y is a cell line derived from human neuroblastoma. It is one of the most widely used in vitro models to study Parkinson's disease. Surprisingly, it has been found that it does not develop a dopaminergic phenotype after differentiation, questioning its usefulness as a Parkinson's model. There are other in vitro models with better dopaminergic characteristics. BE (2)-M17 is a human neuroblastoma cell line that differentiates when treated with retinoic acid. We compared the dopaminergic and serotonergic properties of both cell lines. BE (2)-M17 has higher basal levels of dopaminergic markers and acquires a serotonergic phenotype during differentiation while maintaining the dopaminergic phenotype. SH-SY5Y has higher basal levels of serotonergic markers but does not acquire a dopaminergic phenotype upon differentiation.

Nicotine suppresses Parkinson's disease like phenotypes induced by Synphilin-1 overexpression in Drosophila melanogaster by increasing tyrosine hydroxylase and dopamine levels.

It has been observed that there is a lower Parkinson's disease (PD) incidence in tobacco users. Nicotine is a cholinergic agonist and is the principal psychoactive compound in tobacco linked to cigarette addiction. Different studies have shown that nicotine has beneficial effects on sporadic and genetic models of PD. In this work we evaluate nicotine's protective effect in a Drosophila melanogaster model for PD where Synphilin-1 (Sph-1) is expressed in dopaminergic neurons. Nicotine has a moderate effect on dopaminergic neuron survival that becomes more evident as flies age. Nicotine is beneficial on fly survival and motility increasing tyrosine hydroxylase and dopamine levels, suggesting that cholinergic agonists may promote survival and metabolic function of the dopaminergic neurons that express Sph-1. The Sph-1 expressing fly is a good model for the study of early-onset phenotypes such as olfaction loss one of the main non-motor symptom related to PD. Our data suggest that nicotine is an interesting therapeutic molecule whose properties should be explored in future research on the phenotypic modulators of the disease and for the development of new treatments.

Studying the Contribution of Serotonin to Neurodevelopmental Disorders. Can This Fly?

Serotonin is a biogenic amine that acts as neurotransmitter in different brain regions and is involved in complex behaviors, such as aggression or mood regulation. Thus, this amine is found in defined circuits and activates specific receptors in different target regions. Serotonin actions depend on extracellular levels of this amine, which are regulated by its synthetic enzymes and the plasma membrane transporter, SERT. Serotonin acts also as a neurotrophic signal in ontogeny and in the mature brain, controlling cell proliferation, differentiation, neurogenesis, and neural plasticity. Interestingly, early alterations in serotonergic signaling have been linked to a diversity of neurodevelopmental disorders, including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), or mental illnesses like schizophrenia or depression. It has been proposed that given the complex and numerous actions of serotonin, animal models could better serve to study the complexity of serotonin actions, while providing insights on how hindering serotonergic signaling could contribute to brain disorders. In this mini-review, it will be examined what the general properties of serotonin acting as a neurotransmitter in animals are, and furthermore, whether it is possible that Drosophila could be used to study the contribution of this amine to neurodevelopmental and mental disorders.