Amyotrophic lateral sclerosis patient iPSC-derived astrocytes impair autophagy via non-cell autonomous mechanisms
Open accessAbstract
Amyotrophic lateral sclerosis, a devastating neurodegenerative disease, is characterized by the progressive loss of motor neurons and the accumulation of misfolded protein aggregates. The latter suggests impaired proteostasis may be a key factor in disease pathogenesis, though the underlying mechanisms leading to the accumulation of aggregates is unclear. Further, recent studies have indicated that motor neuron cell death may be mediated by astrocytes. Herein we demonstrate that ALS patient iPSC-derived astrocytes modulate the autophagy pathway in a non-cell autonomous manner. We demonstrate cells treated with patient derived astrocyte conditioned medium demonstrate decreased expression of LC3-II, a key adapter protein required for the selective degradation of p62 and ubiquitinated proteins targeted for degradation. We observed an increased accumulation of p62 in cells treated with patient conditioned medium, with a concomitant increase in the expression of SOD1, a protein associated with the development of ALS. Activation of autophagic mechanisms with Rapamycin reduces the accumulation of p62 puncta in cells treated with patient conditioned medium. These data suggest that patient astrocytes may modulate motor neuron cell death by impairing autophagic mechanisms, and the autophagy pathway may be a useful target in the development of novel therapeutics.
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Conditioned medium from astrocytes differentiated from patient-derived iPSC lines (two with C9orf72 expansion mutations) applied to HEK293T cells reduces LC3-II while increasing SQSTM1 levels, suggesting non-cell autonomous inhibition of autophagy by astrocytes in ALS.
“In addition, conditioned medium from astrocytes differentiated from patient-derived iPSC lines (two of which harbor C9orf72 expansion mutations) applied to HEK293T cells reduces LC3-II while increasing SQSTM1 levels [181], suggesting non-cell autonomous inhibition of autophagy by astrocytes in ALS.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [181]
Astrocytes are both necessary and sufficient for neurodegeneration in this ALS model.
“implying that astrocytes are both necessary and sufficient for neurodegeneration in this ALS model.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [181]
Conditioned media from SOD1-expressing astrocytes is toxic to cultured human motor neurons in vitro.
“conditioned media from SOD1-expressing astrocytes is toxic to cultured human motor neurons in vitro [181,415]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [181]
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“In addition, conditioned medium from astrocytes differentiated from patient-derived iPSC lines (two of which harbor C9orf72 expansion mutations) applied to HEK293T cells reduces LC3II while increasing SQSTM1 levels [181], suggesting non-cell autonomous inhibition of autophagy by astrocytes in ALS.”
BackgroundMandrioli, J., D’Amico, R., Zucchi, E., Gessani, A., Fini, N., Fasano, A., Caponnetto, C., Chiò, A., Dalla Bella, E., Lunetta, C., et al. (2018) · Medicine · doi:10.1097/md.0000000000011119 · Cited by 128 · see citing works
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- Authors
- Madill, M., McDonagh, K., Ma, J., Vajda, A., McLoughlin, P., O’Brien, T., Hardiman, O., & Shen, S.
- Affiliations
- Ollscoil na Gaillimhe – University of Galway (IE)
- Hebei Medical University (CN)
- Trinity College Dublin (IE)
- Corresponding author
- Hardiman, Orla
- Shen, Sanbing
- Venue
- Molecular Brain
- Published
- 2017-06-13
- Volume
- 10
- Issue
- 1
- Pages
- 22-22
- ISSN
- 1756-6606 (ISSN-L)
- PMC
- PMC5470320
- OpenAlex
- W2624682934
- Cited by
- 134
- References
- 48
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 16 · 2023: 15 · 2022: 12 · 2021: 20 · 2020: 22 · 2019: 17 · 2018: 13 · 2017: 4
- FWCI
- 10.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Brain (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (acceptedVersion, cc-by-nc-nd)
- Arrow@dit (Dublin Institute of Technology) (acceptedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion)
- ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (submittedVersion, cc-by-nc)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, cc-by-nc-sa)
- Research Repository UCD (University College Dublin) (cc-by-nc)
- Funders
- Science Foundation Ireland (09/SRC/B1794s1 and 13/IA/1787)
- National University of Ireland, Galway (RSU002)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, iPSC-derived astrocytes, autophagy, non-cell-autonomous mechanisms, conditioned medium, LC3-II, SOD1, motor neuron degeneration, proteostasis, rapamycin, neurodegeneration
- MeSH terms
- Autophagy-Related Proteins, Sequestosome-1 Protein, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Astrocytes, Autophagy, Cell Survival, Female, Humans, Male, Middle Aged, Motor Neurons, Culture Media, Conditioned, Sirolimus, Mice, Young Adult, Induced Pluripotent Stem Cells, HEK293 Cells, Cellular Reprogramming
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