Parkinson’s disease (PD) is a chronic and progressive neurodegeneration of dopamine neurons in the substantia nigra. The reason for the death of these neurons is unclear; however, studies have demonstrated the potential involvement of mitochondria, endoplasmic reticulum, α-synuclein or dopamine levels in contributing to cellular oxidative stress as well as PD symptoms. Even though those papers had separately described the individual roles of each element leading to neurodegeneration, recent publications suggest that neurodegeneration is the product of various cellular interactions. This review discusses the role of oxidative stress in mediating separate pathological events that together, ultimately result in cell death in PD. Understanding the multi-faceted relationships between these events, with oxidative stress as a common denominator underlying these processes, is needed for developing better therapeutic strategies.

Parkinson's disease (PD) is characterized by the selective loss of dopamine neurons in the substantia nigra; however, the mechanism of neurodegeneration in PD remains unclear. A subset of familial PD is linked to mutations in PARK2 and PINK1, which lead to dysfunctional mitochondria-related proteins Parkin and PINK1, suggesting that pathways implicated in these monogenic forms could play a more general role in PD. We demonstrate that the identification of disease-related phenotypes in PD-patient-specific induced pluripotent stem cell (iPSC)-derived midbrain dopamine (mDA) neurons depends on the type of differentiation protocol utilized. In a floor-plate-based but not a neural-rosette-based directed differentiation strategy, iPSC-derived mDA neurons recapitulate PD phenotypes, including pathogenic protein accumulation, cell-type-specific vulnerability, mitochondrial dysfunction, and abnormal neurotransmitter homeostasis. We propose that these form a pathogenic loop that contributes to disease. Our study illustrates the promise of iPSC technology for examining PD pathogenesis and identifying therapeutic targets.

The gastrointestinal (GI) tract is a highly complex organ composed of the intestinal epithelium layer, intestinal microbiota, and local immune system. Intestinal microbiota residing in the GI tract engages in a mutualistic relationship with the host. Different sections of the GI tract contain distinct proportions of the intestinal microbiota, resulting in the presence of unique bacterial products in each GI section. The intestinal microbiota converts ingested nutrients into metabolites that target either the intestinal microbiota population or host cells. Metabolites act as messengers of information between the intestinal microbiota and host cells. The intestinal microbiota composition and resulting metabolites thus impact host development, health, and pathogenesis. Many recent studies have focused on modulation of the gut microbiota and their metabolites to improve host health and prevent or treat diseases. In this review, we focus on the production of microbial metabolites, their biological impact on the intestinal microbiota composition and host cells, and the effect of microbial metabolites that contribute to improvements in inflammatory bowel diseases and metabolic diseases. Understanding the role of microbial metabolites in protection against disease might offer an intriguing approach to regulate disease.

Serotonin (5-HT) neurons, the major components of the raphe nuclei, arise from ventral hindbrain progenitors. Based on anatomical location and axonal projection, 5-HT neurons are coarsely divided into rostral and caudal groups. Here, we propose a novel strategy to generate hindbrain 5-HT neurons from human pluripotent stem cells (hPSCs), which involves the formation of ventral-type neural progenitor cells and stimulation of the hindbrain 5-HT neural development. A caudalizing agent, retinoid acid, was used to direct the cells into the hindbrain cell fate. Approximately 30%-40% of hPSCs successfully developed into 5-HT-expressing neurons using our protocol, with the majority acquiring a caudal rhombomere identity (r5-8). We further modified our monolayer differentiation system to generate 5-HT neuron-enriched hindbrain-like organoids. We also suggest downstream applications of our 5-HT monolayer and organoid cultures to study neuronal response to gut microbiota. Our methodology could become a powerful tool for future studies related to 5-HT neurotransmission.

Developmental information aids stem cell biologists in producing tissue-specific cells. Recapitulation of the developmental profile of a specific cell type in an in vitro stem cell system provides a strategy for manipulating cell-fate choice during the differentiation process. Nurr1 and Foxa2 are potential candidates for genetic engineering to generate midbrain-type dopamine (DA) neurons for experimental and therapeutic applications in Parkinson’s disease (PD), as forced expression of these genes in neural stem/precursor cells (NPCs) yields cells with a complete battery of midbrain DA neuron-specific genes. However, simple overexpression without considering their expression pattern in the developing midbrain tends to generate DA cells without adequate neuronal maturation and long-term maintenance of their phenotype in vitro and in vivo after transplantation. We here show that the physiological levels and timing of Nurr1 and Foxa2 expression can be replicated in NPCs by choosing the right vectors and promoters. Controlled expression combined with a strategy for transgene expression maintenance induced generation of fully mature midbrain-type DA neurons. These findings demonstrate the feasibility of cellular engineering for artificial cell-fate specification.

The R-spondin (RSPO) family of proteins potentiate canonical WNT/β-catenin signaling and may provide a mechanism to fine-tune the strength of canonical WNT signaling. Although several in vitro studies have clearly demonstrated the potentiation of canonical WNT signaling by RSPOs, whether this potentiation actually occurs in normal development and tissue function in vivo still remains poorly understood. Here, we provide clear evidence of the potentiation of canonical WNT signaling by RSPO during mouse facial development by analyzing compound Wnt9b and Rspo2 gene knockout mice and utilizing ex vivo facial explants. Wnt9b;Rspo2 double mutant mice display facial defects and dysregulated gene expression pattern that are significantly more severe than and different from those of Wnt9b or Rspo2 null mutant mice. Furthermore, we found suggestive evidence that the LGR4/5/6 family of the RSPO receptors may play less critical roles in WNT9b:RSPO2 cooperation. Our results suggest that RSPO-induced cooperation is a key mechanism for fine-tuning canonical WNT/β-catenin signaling in mouse facial development.