The raphe nuclei are the early lesion site of gastric α-synuclein propagation to the substantia nigra.

Parkinson's disease (PD) is a neurodegeneration disease with α-synuclein accumulated in the substantia nigra pars compacta (SNpc) and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with PD. Exploring the pathology at an early stage contributes to the development of the disease-modifying strategy. Although the "gut-brain" hypothesis is proposed to explain the underlying mechanism, where the earlier lesioned site in the brain of gastric α-synuclein and how α-synuclein further spreads are not fully understood. Here we report that caudal raphe nuclei (CRN) are the early lesion site of gastric α-synuclein propagating through the spinal cord, while locus coeruleus (LC) and substantia nigra pars compacta (SNpc) were further affected over a time frame of 7 months. Pathological α-synuclein propagation via CRN leads to neuron loss and disordered neuron activity, accompanied by abnormal motor and non-motor behavior. Potential neuron circuits are observed among CRN, LC, and SNpc, which contribute to the venerability of dopaminergic neurons in SNpc. These results show that CRN is the key region for the gastric α-synuclein spread to the midbrain. Our study provides valuable details for the "gut-brain" hypothesis and proposes a valuable PD model for future research on early PD intervention.

Discovery of 3, 6-disubstituted isobenzofuran-1(3H)-ones as novel inhibitors of monoamine oxidases.

Monoamine oxidases A and B (MAO-A and MAO-B) play important roles in biogenic amine metabolism, oxidative stress, and chronic inflammation. Particularly, MAO-B selective inhibitors are promising therapeutic choices for the treatment of neurodegenerative diseases, such as Pakinson's disease and Alzheimer's disease. Herein, novel 3,6-disubstituted isobenzofuran-1(3H)-ones were designed, synthesized and evaluated in vitro as inhibitors of monoamine oxidases A and B. Structure-activity relationships were investigated, and all of the compounds with (R)-3-hydroxy pyrrolidine moiety on the 6-position displayed preferable inhibition toward the MAO-B isoform. Among them, compounds 6c with a 4'-fluorobenzyl ring and 6m bearing a 3',4'-difluorobenzyl ring on the 3-position were the most potent MAO-B inhibitors with IC50 values of 0.35 µM and 0.32 µM, respectively. The binding mode of compound 6m in MAO-B was predicted by CDOCKER program, revealing that (R)-3-hydroxypyrrolidine moiety is a critical structural feature for this series of MAO-B inhibitors. Compound 6m could serve as a new template structure for developing potent and selective MAO-B inhibitors.

The neuroinflammatory role of glucocerebrosidase in Parkinson's disease.

The lysosomal enzyme glucocerebrosidase (GCase), encoded by the GBA1 gene, is a membrane-associated protein catalyzing the cleavage of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Homologous GBA1 mutations cause Gaucher disease (GD) and heterologous mutations cause Parkinson's disease (PD). Importantly, heterologous GBA1 mutations are recognized as the second risk factor of PD. The pathological features of PD are Lewy neurites (LNs) and Lewy bodies (LBs) composed of pathological α-synuclein. Oxidative stress, inflammatory response, autophagic impairment, and α-synuclein accumulation play critical roles in PD pathogenic cascades, but the pathogenesis of PD has not yet been fully elucidated. What's more, PD treatment drugs can only relieve symptoms to a certain extent, but cannot alleviate neurodegenerative progression. Therefore, it's urgent to explore new targets that can alleviate the neurodegenerative process. Deficient GCase can cause lysosomal dysfunction, obstructing the metabolism of α-synuclein. Meanwhile, GCase dysfunction causes accumulation of its substrates, leading to lipid metabolism disorders. Subsequently, astrocytes and microglia are activated, releasing amounts of pro-inflammatory mediators and causing extensive neuroinflammation. All these cascades can induce neuron damage and death, eventually promoting PD pathology. This review aims to summarize these points and the potential of GCase as an original target to provide some ideas for elucidating the pathogenesis of PD.