SummaryRecent advances in generating three-dimensional (3D) organoid systems from stem cells offer new possibilities for disease modeling and drug screening because organoids can recapitulate aspects of in vivo architecture and physiology. In this study, we generate isogenic 3D midbrain organoids with or without a Parkinson's disease-associated LRRK2 G2019S mutation to study the pathogenic mechanisms associated with LRRK2 mutation. We demonstrate that these organoids can recapitulate the 3D pathological hallmarks observed in patients with LRRK2-associated sporadic Parkinson's disease. Importantly, analysis of the protein-protein interaction network in mutant organoids revealed that TXNIP, a thiol-oxidoreductase, is functionally important in the development of LRRK2-associated Parkinson's disease in a 3D environment. These results provide proof of principle for the utility of 3D organoid-based modeling of sporadic Parkinson's disease in advancing therapeutic discovery.

No abstract

Platelets play an essential role in hemostasis through aggregation and adhesion to vascular injury sites but their unnecessary activation can often lead to thrombotic diseases. Upon exposure to physical or biochemical stimuli, remarkable platelet shape changes precede aggregation or adhesion. Platelets shape changes facilitate the formation and adhesion of platelet aggregates, but are readily reversible in contrast to the irrevocable characteristics of aggregation and adhesion. In this dynamic phenomenon, complex molecular signaling pathways and a host of diverse cytoskeleton proteins are involved. Platelet shape change is easily primed by diverse pro-thrombotic xenobiotics and stimuli, and its inhibition can modulate thrombosis, which can ultimately contribute to the development or prevention of thrombotic diseases. In this review, we discussed the current knowledge on the mechanisms of platelet shape change and also pathological implications and therapeutic opportunities for regulating the related cytoskeleton dynamics.

Neurodegenerative diseases are incurable and debilitating conditions characterized by the deterioration of brain function. Most brain disease models rely on human post‐mortem brain tissue, non‐human primate tissue, or in vitro two‐dimensional (2D) experiments. Resource limitations and the complexity of the human brain are some of the reasons that make suitable human neurodegenerative disease models inaccessible. However, recently developed three‐dimensional (3D) brain organoids derived from pluripotent stem cells (PSCs), including embryonic stem cells and induced PSCs, may provide suitable models for the study of the pathological features of neurodegenerative diseases. In this review, we provide an overview of existing 3D brain organoid models and discuss recent advances in organoid technology that have increased our understanding of brain development. Moreover, we explain how 3D organoid models recapitulate aspects of specific neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and explore the utility of these models, for therapeutic applications.

Alzheimer’s disease (AD) is associated with progressive neuronal degeneration as amyloid-beta (Aβ) and tau proteins accumulate in the brain. Glial cells were recently reported to play an important role in the development of AD. However, little is known about the role of oligodendrocytes in AD pathogenesis. Here, we describe a disease-associated subpopulation of oligodendrocytes that is present during progression of AD-like pathology in the male AppNL-G-F and male 5xFAD AD mouse brains and in postmortem AD human brains using single-cell RNA sequencing analysis. Aberrant Erk1/2 signaling was found to be associated with the activation of disease-associated oligodendrocytes (DAOs) in male AppNL-G-F mouse brains. Notably, inhibition of Erk1/2 signaling in DAOs rescued impaired axonal myelination and ameliorated Aβ-associated pathologies and cognitive decline in the male AppNL-G-F AD mouse model.