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Sökning: onr:"swepub:oai:DiVA.org:umu-215749" > Analysis of proteom...

Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis

Tsioras, Konstantinos (författare)
The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
Smith, Kevin C. (författare)
The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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
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
Williams, Chloe (författare)
Umeå universitet,Institutionen för integrativ medicinsk biologi (IMB)
McKenna, Elizabeth D. (författare)
The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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
Wilen, Anika P. (författare)
The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
Hark, Timothy J. (författare)
The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
Marklund, Stefan L. (författare)
Umeå universitet,Klinisk kemi
Ostrow, Lyle W. (författare)
Department of Neurology, Lewis Katz School of Medicine at Temple University, PA, Philadelphia, United States
Gilthorpe, Jonathan D. (författare)
Umeå universitet,Institutionen för integrativ medicinsk biologi (IMB)
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
Kalb, Robert G. (författare)
The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
Savas, Jeffrey N. (författare)
The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States
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.
Ingår i: Cell Reports. - : Elsevier. - 2211-1247. ; 42:10
Relaterad länk:
https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
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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