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Analysis of proteom...
Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis
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- Tsioras, Konstantinos (författare)
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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- Smith, Kevin C. (författare)
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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- Edassery, Seby L. (författare)
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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- Garjani, Mehraveh (författare)
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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- Li, Yichen (författare)
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, CA, Los Angeles, United States
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- Williams, Chloe (författare)
- Umeå universitet,Institutionen för integrativ medicinsk biologi (IMB)
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- McKenna, Elizabeth D. (författare)
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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- Guo, Wenxuan (författare)
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, CA, Los Angeles, United States
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- Wilen, Anika P. (författare)
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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- Hark, Timothy J. (författare)
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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- Marklund, Stefan L. (författare)
- Umeå universitet,Klinisk kemi
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- Ostrow, Lyle W. (författare)
- Department of Neurology, Lewis Katz School of Medicine at Temple University, PA, Philadelphia, United States
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- Gilthorpe, Jonathan D. (författare)
- Umeå universitet,Institutionen för integrativ medicinsk biologi (IMB)
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- Ichida, Justin K. (författare)
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, CA, Los Angeles, United States
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- Kalb, Robert G. (författare)
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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- Savas, Jeffrey N. (författare)
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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- Kiskinis, Evangelos (författare)
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States; Simpson Querrey Institute, Northwestern University, IL, Chicago, United States; Department of Neuroscience, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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(creator_code:org_t)
- Elsevier, 2023
- 2023
- Engelska.
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Ingår i: Cell Reports. - : Elsevier. - 2211-1247. ; 42:10
- Relaterad länk:
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs. The interactome of VCP is altered in mutSOD1 MNs in vitro, while VCP selectively accumulates in the affected motor cortex of ALS-SOD1 patients. Overexpression of VCP rescues mutSOD1 toxicity in MNs in vitro and in a C. elegans model in vivo, in part due to its ability to modulate the degradation of insoluble mutSOD1. Our results demonstrate that VCP contributes to mutSOD1-dependent degeneration, link two distinct ALS-causal genes, and highlight selective protein degradation impairment in ALS pathophysiology.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
Nyckelord
- ALS
- amyotrophic lateral sclerosis
- CP: Neuroscience
- CP: Stem cell research
- iPSCs
- motor neurons
- protein degradation
- SILAC-based mass spectrometry
- SOD1
- ubiquitin
- VCP/p97
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Tsioras, Konstan ...
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Smith, Kevin C.
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Edassery, Seby L ...
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Garjani, Mehrave ...
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Li, Yichen
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Williams, Chloe
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visa fler...
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McKenna, Elizabe ...
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Guo, Wenxuan
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Wilen, Anika P.
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Hark, Timothy J.
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Marklund, Stefan ...
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Ostrow, Lyle W.
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Gilthorpe, Jonat ...
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Ichida, Justin K ...
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Kalb, Robert G.
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Savas, Jeffrey N ...
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Kiskinis, Evange ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Cell och molekyl ...
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NATURVETENSKAP
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och Cellbiologi
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Cell Reports
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