Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS

Autor: Hall, Claire E, Yao, Zhi, Choi, Minee, Tyzack, Giulia E, Serio, Andrea, Luisier, Raphaelle, Harley, Jasmine, Preza, Elisavet, Arber, Charlie, Crisp, Sarah J, Watson, P Marc D, Kullmann, Dimitri M, Abramov, Andrey Y, Wray, Selina, Burley, Russell, Loh, Samantha HY, Martins, L Miguel, Stevens, Molly M, Luscombe, Nicholas M, Sibley, Christopher R, Lakatos, Andras, Ule, Jernej, Gandhi, Sonia, Patani, Rickie
Přispěvatelé: Crisp, Sarah [0000-0002-0007-7775], Loh, Sam [0000-0001-5073-6065], Lakatos, Andras [0000-0002-1301-2292], Apollo - University of Cambridge Repository
Jazyk: angličtina
Předmět:
amyotrophic lateral sclerosis (ALS)
Mutation/genetics
Cell Survival
TDP-43
Neurogenesis
Induced Pluripotent Stem Cells
Endoplasmic Reticulum
Models
Biological
AMYOTROPHIC-LATERAL-SCLEROSIS
GLUTAMATE
ENDOPLASMIC-RETICULUM STRESS
Valosin Containing Protein
Report
Mitochondria/metabolism
REVEALS
disease modeling
Humans
Amyotrophic Lateral Sclerosis/metabolism
Endoplasmic Reticulum/metabolism
lcsh:QH301-705.5
Nerve Degeneration/pathology
Membrane Potential
Mitochondrial
Motor Neurons
DNA-Binding Proteins/metabolism
Science & Technology
MUTATIONS
Amyotrophic Lateral Sclerosis
Motor Neurons/pathology
Cell Biology
ER STRESS
Endoplasmic Reticulum Stress
Mitochondria
MUTANT SOD1
DNA-Binding Proteins
Induced Pluripotent Stem Cells/metabolism
Oxidative Stress
Phenotype
Synapses/pathology
lcsh:Biology (General)
astrocytes (ACs)
Astrocytes/pathology
Astrocytes
Mutation
Nerve Degeneration
Synapses
motor neurons (MNs)
induced pluripotent stem cells (iPSCs)
Life Sciences & Biomedicine
Valosin Containing Protein/metabolism
Zdroj: Cell Reports
Cell Reports, Vol 19, Iss 9, Pp 1739-1749 (2017)
Hall, C E, Yao, Z, Choi, M, Tyzack, G E, Serio, A, Luisier, R, Harely, J, Preza, E, Arber, C, Crisp, S J, Watson, P M D, Kullmann, D, Abramov, A, Wray, S, Burley, R, Loh, S HY, Martins, M, Stevens, M, Luscombe, N M, Sibley, C R, Lakatos, A, Ule, J, Gandhi, S & Patani, R 2017, ' Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS ', Cell Reports, vol. 19, no. 9, pp. 1739-1749 . https://doi.org/10.1016/j.celrep.2017.05.024
Hall, C E, Yao, Z, Choi, M, Tyzack, G E, Serio, A, Luisier, R, Harley, J, Preza, E, Arber, C, Crisp, S J, Watson, P M D, Kullmann, D M, Abramov, A Y, Wray, S, Burley, R, Loh, S H Y, Martins, L M, Stevens, M M, Luscombe, N M, Sibley, C R, Lakatos, A, Ule, J, Gandhi, S & Patani, R 2017, ' Progressive motor neuron pathology and the role of astrocytes in a Human Stem Cell Model of VCP-Related ALS ', Cell Reports, vol. 19, no. 9, pp. 1739-1749 . https://doi.org/10.1016/j.celrep.2017.05.024
ISSN: 2211-1247
DOI: 10.1016/j.celrep.2017.05.024
Popis: Summary Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS.
Graphical Abstract
Highlights • Robust and enriched motor neurogenesis and astrogliogenesis from human iPSCs • VCP-mutant motor neurons show TDP-43 mislocalization and ER stress as early pathogenic events • VCP-mutant astrocytes exhibit a cell-autonomous survival phenotype • VCP-mutations perturb the ability of astrocytes to support motor neuron survival
Hall et al. use iPSCs to examine the sequence of events by which motor neurons degenerate in a genetic form of ALS. They find that astrocytes, a type of supportive cell, also degenerate under these conditions. The ALS-causing mutation disrupts the ability of astrocytes to promote survival of motor neurons.
Databáze: OpenAIRE
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