With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its "double-edged sword", autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.

https://www.mdpi.com/1422-0067/21/19/7174/pdf

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

Parkinson's disease (PD) is a neurodegenerative disorder caused by the depletion of dopaminergic neurons in the basal ganglia, the movement center of the brain. Approximately 60,000 people are diagnosed with PD in the United States each year. Although the direct cause of PD can vary, accumulation of oxidative stress-induced neuronal damage due to increased production of reactive oxygen species (ROS) or impaired intracellular antioxidant defenses invariably occurs at the cellular levels. Pharmaceuticals such as dopaminergic prodrugs and agonists can alleviate some of the symptoms of PD. Currently, however, there is no treatment to halt the progression of PD pathology. Due to the nature of PD, a long and progressive neurodegenerative process, strategies to prevent or delay PD pathology may be well suited to lifestyle changes like dietary modification with antioxidant-rich foods to improve intracellular redox homeostasis. In this review, we discuss cellular and genetic factors that increase oxidative stress in PD. We also discuss neuroprotective roles of dietary antioxidants including vitamin C, vitamin E, carotenoids, selenium, and polyphenols along with their potential mechanisms to alleviate PD pathology.

Dietary Antioxidants and Parkinson's Disease.

Current approaches in CRISPR-Cas9 mediated gene editing for biomedical and therapeutic applications.

Human brain organoid models that recapitulate the physiology and complexity of the human brain have a great potential for in vitro disease modeling, in particular for neurodegenerative diseases, such as Parkinson disease. In the present study, we compare single-cell RNA-sequencing data of human midbrain organoids to the developing human embryonic midbrain. We demonstrate that the in vitro model is comparable to its in vivo equivalents in terms of developmental path and cellular composition. Moreover, we investigate the potential of midbrain organoids for modeling early developmental changes in Parkinson disease. Therefore, we compare the single-cell RNA-sequencing data of healthy-individual-derived midbrain organoids to their isogenic LRRK2-p.Gly2019Ser-mutant counterparts. We show that the LRRK2 p.Gly2019Ser variant alters neurodevelopment, resulting in an untimely and incomplete differentiation with reduced cellular variability. Finally, we present four candidate genes, APP, DNAJC6, GATA3, and PTN, that might contribute to the LRRK2-p.Gly2019Ser-associated transcriptome changes that occur during early neurodevelopment. 

http://www.cell.com/article/S000292972100464X/pdf

Midbrain organoids mimic early embryonic neurodevelopment and recapitulate LRRK2-p.Gly2019Ser-associated gene expression

Environmental toxins are harmful substances detrimental to humans. Constant exposure to these fatal neurotoxins can cause various neurodegenerative disorders. Although poisonous, specific neurotoxins at optimal concentrations mimic the clinical features of neurodegenerative diseases in several animal models. Such chemically-induced model systems are beneficial in deciphering the molecular mechanisms of neurodegeneration and drug screening for these disorders. One such neurotoxin is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a widely used chemical that recapitulates Parkinsonian features in various animal models. Apart from MPTP, other neurotoxins like 6-hydroxydopamine (6-OHDA), paraquat, rotenone also induce specific clinical features of Parkinson's disease in animal models. These chemically-induced Parkinson's disease models are playing a crucial role in understanding Parkinson's disease onset, pathology, and novel therapeutics. In this review, we provide a concise overview of various neurotoxins that can recapitulate Parkinsonian features in different in vivo and in vitro model systems specifically focusing on the different treatment methodologies of neurotoxins.

Chemically induced models of Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) G2019S is a relatively common mutation, associated with 1–3% of Parkinson’s disease (PD) cases worldwide. G2019S is hypothesized to increase LRRK2 kinase activity. Dopaminergic neurons derived from induced pluripotent stem cells of PD patients carrying LRRK2 G2019S are reported to have several phenotypes compared to wild type controls, including increased activated caspase-3 and reactive oxygen species (ROS), autophagy dysfunction, and simplification of neurites. The common marmoset is envisioned as a candidate nonhuman primate species for comprehensive modeling of genetic mutations. Here, we report our successful use of CRISPR/Cas9 with repair template-mediated homology directed repair to introduce the LRRK2 G2019S mutation, as well as a truncation of the LRRK2 kinase domain, into marmoset embryonic and induced pluripotent stem cells. We found that, similar to humans, marmoset LRRK2 G2019S resulted in elevated kinase activity. Phenotypic evaluation after dopaminergic differentiation demonstrated LRRK2 G2019S-mediated increased intracellular ROS, decreased neuronal viability, and reduced neurite complexity. Importantly, these phenotypes were not observed in clones with LRRK2 truncation. These results demonstrate the feasibility of inducing monogenic mutations in common marmosets and support the use of this species for generating a novel genetic-based model of PD that expresses physiological levels of LRRK2 G2019S.

/pdf/in-vitro-crispr-cas9-directed-gene-editing-to-model-lrrk2-20dxggk1kh.pdf

In Vitro CRISPR/Cas9-Directed Gene Editing to Model LRRK2 G2019S Parkinson’s Disease in Common Marmosets

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In Vitro CRISPR/Cas9-Directed Gene Editing to Model LRRK2 G2019S Parkinson’s Disease in Common Marmosets