[Research progress of neurobiological function of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline].

1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (Sal) is a kind of catechol isoquinoline compound, which mainly exists in mammalian brain and performs a variety of biological functions. Through in vivo metabolism, Sal can be transformed into endogenous neurotoxins and can participate the occurrence of Parkinson's disease (PD). This has attracted widespread concern of researchers. Recently, many research works have shown that Sal may lead to alcohol addiction and regulate hormone release of the neuroendocrine system, which indicated that it is a potential regulator of dopaminergic neurons. In this paper, we discuss the neural functions of Sal on the above aspects, and wish to provide some theoretical supports for further research on its mechanism.

Down-Regulation of m6A mRNA Methylation Is Involved in Dopaminergic Neuronal Death.

N6-Methyladenosine (m6A) is the most prevalent internal modification that occurs in the mRNA of eukaryotes and plays a vital role in the post-transcriptional regulation. Recent studies highlighted the biological significance of m6A modification in the nervous system, and its dysregulation has been shown to be related to degenerative and neurodevelopmental diseases. Parkinson's disease (PD) is a common age-related neurological disorder with its pathogenesis still not fully elucidated. Reports have shown that epigenetic mechanisms including DNA methylation and histone acetylation, which alter gene expression, are associated with PD. In this study, we found that global m6A modification of mRNAs is down-regulated in 6-OHDA-induced PC12 cells and the striatum of PD rat brain. To further explore the relationship between m6A mRNA methylation and molecular mechanism of PD, we decreased m6A in dopaminergic cells by overexpressing a nucleic acid demethylase, FTO, or by m6A inhibitor. The results showed that m6A reduction could induce the expression of N-methyl-d-aspartate (NMDA) receptor 1, and elevate oxidative stress and Ca2+ influx, resulting in dopaminergic neuron apoptosis. Collectively, m6A modification may play a vital role in the death of dopaminergic neuron, which provides a novel view of mRNA methylation to understand the epigenetic regulation of Parkinson's disease.

Isolation and Sequencing of Salsolinol Synthase, an Enzyme Catalyzing Salsolinol Biosynthesis.

Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), a derivate of dopamine, is suspected to be the most probable neurotoxin in the degeneration of dopaminergic neurons. Numerous hypotheses regarding its pathophysiological roles have been raised, especially related to Parkinson's disease and alcohol addiction. In the mammalian brain, salsolinol may be enzymatically synthesized by salsolinol synthase from dopamine and acetaldehyde. However, the direct evidence of its biosynthesis was still missing. In this study, we purified salsolinol synthase from rat brain by a systematical procedure involving acid precipitation, ultrafiltration, and hydrophilic interaction chromatography. The molecular weight of salsolinol synthase determined by MALDI-TOF MS is 8622.29 Da, comprising 77 amino acids (MQIFVKTLTG KTITLEVEPS DTIKNVKAKI QDKEGIPPDQ QRLIFAGKQL EDGRTLSDYN IQKKSTLHLV LRLRVDY). Homology analysis showed that the enzyme is a ubiquitin-like protein, with a difference of four amino acids, which suggests it is a novel protein. After it was overexpressed in eukaryotic cells, the production of salsolinol was significantly increased as compared with control, confirming the catalytic function of this enzyme. To our knowledge, it is the first systematic purification and sequencing of salsolinol synthase. Together, this work reveals a formerly anonymous protein and urges further exploration of its possible prognostic value and implications in Parkinson's disease and other related disorders.

Changes in salsolinol production and salsolinol synthase activity in Parkinson's disease model.

Salsolinol is an endogenous neurotoxin derived from dopamine, and has been proved to cause the apoptosis of the dopaminergic neurons involved in the pathogenesis of Parkinson's disease (PD). Salsolinol synthase is the key enzyme in the biosynthesis of salsolinol, and its activity exists in most regions of rat brain. However, the activity distribution and its catalyzed function in vivo are still unknown. On the basis of the chromatographic assay established previously, we investigated the activity of salsolinol synthase and salsolinol production in both cell and rat model of PD induced by 6-hydroxydopamine (6-OHDA). The results show that the enzymatic activity increases in cell model and in the striatum region of PD rat brain. Nevertheless, there is a reduction of activity in hippocampus, cortex, and midbrain of PD model when compared with control. Conversely, the level of salsolinol was significantly increased in the midbrain region. Together, these results indicate the relationship between the oxidative stress induced by 6-OHDA and the activity of salsolinol synthase, suggesting the correlation of the endogenous neurotoxin and Parkinson's disease. Further research will provide more evidence and clarity on the function of Sal synthase.

m6A RNA Modification Determines Cell Fate by Regulating mRNA Degradation.

Emerging evidence suggests that epitranscriptional modifications influence multiple cellular processes. N6-methyladenosine (m6A), as the most abundant reversible methylation of mRNA, has also been reported to play critical roles in modulating embryonic stem cell differentiation and somatic cell reprogramming by regulating gene expression. This review examined the characteristics of m6A, including the distribution profile and currently discovered "writer," "eraser," and "reader" proteins. Moreover, the hypothesis is proposed that m6A could influence cell fate determination, and the underlying mechanisms are due to the related mRNA degradation, causing weakening of previous cell characteristics and eventually leading them to develop into the reverse direction (pluripotency or differentiation state). Accordingly, m6A modifications presented its potential role in cell fate determination, which provides new insights into understanding the mechanisms of various diseases.