Abstract
Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.
Highlights
Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD) represent a huge social and economic burden due to their high incidence, the severity of their symptoms, and the lack of effective disease-modifying therapies
Several readouts may be used for High-throughput screening (HTS), including fluorescence labeling methods for specific molecular targets, reporter-gene luminescent assays for transcriptional activity, mass spectrometry analysis for proteomic changes, and cell-based phenotypic screens [67]
Discovery is being applied from to neurological disorders from cancers, it analyzes the changes in their genefrom expression profiles after treatment utilizesand a collection of transcriptomes obtained cultured human cells, often from canwith bioactive small molecules to discover relationships between the drugs, gene expres- with cers, and it analyzes the changes in their gene expression profiles after treatment sion changes, and the phenotypes exhibited by the cells approach bioactive small molecules to discover relationships between the drugs, geneuses expression a gene signature set consisting of differentially genes (DEGs)
Summary
Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD) represent a huge social and economic burden due to their high incidence, the severity of their symptoms, and the lack of effective disease-modifying therapies. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors have created new methods of modeling neurological diseases in a human context that is just beginning to be exploited for therapeutic purposes. HiPSCs are produced by reprogramming human cells, obtained from tissues such as skin or blood, into a pluripotent state, and differentiated into the desired cell type, e.g., neurons, astrocytes, microglia, or oligodendrocytes. This is achieved by first introducing fate-determining “pluripotency factors” into the human skin or blood cell. While direct conversion (avoiding an intermediate pluripotent state) of cell types, e.g., fibroblasts to neurons, is possible and may retain more epigenetic features [10], this technique does not afford a limitless supply of converted cells the way the hiPSC platform can by expanding the stem cell pool
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