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Modeling Adult‐Onset Neurodegenerative Disorders with Human Neurons through Direct Neuronal Reprogramming
Author(s) -
Yoo Andrew
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.205.1
Subject(s) - reprogramming , biology , neuroscience , neurodegeneration , induced pluripotent stem cell , embryonic stem cell , chromatin , epigenetics , somatic cell , cellular model , neural stem cell , cell type , stem cell , cell , microbiology and biotechnology , cell culture , medicine , disease , pathology , genetics , gene
Studying late‐onset neurodegenerative disorders using human neurons remains a challenging task due to the inaccessibility of live neurons from the affected patients. Neurons from induced pluripotent stem cells (iPSCs) have limited potential to recapitulate cellular processes that occur in aged neurons as the induction of pluripotency resets the cellular age to an embryonic/fetal stage. The ability to generate human neurons that reflect the mature adult state will thus provide a powerful platform to investigate adult‐onset disorders. Brain‐enriched microRNAs (miRNAs), miR‐9/9* and miR‐124 (miR‐9/9*‐124) can function as potent cell fate regulators that can direct cell fate conversion (reprogramming) of non‐neural human somatic cells to neurons. When ectopically expressed in human adult fibroblasts, miR‐9/9*‐124 target multiple components of chromatin modifiers inducing an extensive reconfiguration of the chromatin landscape while erasing the fibroblast fate and promoting the neuronal identity. The miR‐9/9*‐124‐induced state becomes poised to receive inputs from additional subtype‐defining transcription factors (TFs), allowing the generation of specific neuronal subtypes including cortical, striatal, and spinal cord motor neurons. Importantly, for modeling adult‐onset disorders, we found that directly converted neurons preserve the age‐associated epigenetic memory reflecting the age signature of fibroblast donors. We have applied the neuronal conversion method specific for striatal medium spiny neurons (MSNs), the primary cell target that undergoes neurodegeneration in Huntington's disease (HD) in fibroblasts of HD patients (HD‐MSNs). We found that HD‐MSNs manifested hallmarks of adult‐onset HD including the aggregation of Huntingtin protein, increased DNA damage, mitochondrial dysfunction and spontaneous neuronal death in culture. Collectively, our studies demonstrate the potent activity of microRNAs as cell fate regulators and its utility to generate a patient‐derived cellular platform to model adult‐onset neurodegenerative diseases. Support or Funding Information Andrew B and Virginia C. Craig Faculty Fellowship Endowment, Farrell Fund, Cure Alzheimer's Fund (CAF), Mallinckrodt Scholar Award, NIA (RF1AG056296), and NINDH (1R01NS107488) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .