Ziff, OJ;
Patani, R;
(2019)
Harnessing cellular aging in human stem cell models of amyotrophic lateral sclerosis.
Aging Cell
, Article e12862. 10.1111/acel.12862.
(In press).
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Abstract
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition that is invariably fatal, usually within 3 to 5 years of diagnosis. The etiology of ALS remains unresolved and no effective treatments exist. There is therefore a desperate and unmet need for discovery of disease mechanisms to guide novel therapeutic strategies. The single major risk factor for ALS is aging, yet the molecular consequences of cell type-specific aging remain understudied in this context. Induced pluripotent stem cells (iPSCs) have transformed the standard approach of examining human disease, generating unlimited numbers of disease-relevant cells from patients, enabling analysis of disease mechanisms and drug screening. However, reprogramming patient cells to iPSCs reverses key hallmarks of cellular age. Therefore, although iPSC models recapitulate some disease hallmarks, a crucial challenge is to address the disparity between the advanced age of onset of neurodegenerative diseases and the fetal-equivalent maturational state of iPSC-derivatives. Increasing recognition of cell type-specific aging paradigms underscores the importance of heterogeneity in ultimately tipping the balance from a state of compensated dysfunction (clinically pre-symptomatic) to decompensation and progression (irreversible loss of neurological functions). In order to realize the true promise of iPSC technology in ALS, efforts need to prioritize faithfully recapitulating the clinical pathophysiological state, with proportionate emphasis on capturing the molecular sequelae of both cellular age and non-cell-autonomous disease mechanisms within this context.
| Type: | Article |
|---|---|
| Title: | Harnessing cellular aging in human stem cell models of amyotrophic lateral sclerosis |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/acel.12862 |
| Publisher version: | https://doi.org/10.1111/acel.12862 |
| Language: | English |
| Additional information: | © 2018 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | aging, amyotrophic lateral sclerosis, motor neuron disease, neurodegeneration, pluripotent stem cells |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10065029 |
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