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

SUMMARY 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.

• Publication year

  2023

• Venue

  Cell Reports

• Publication date

  2023-09-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.celrep.2023.113160PMID 37776851PMCID 10785776
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis—Frontotemporal Dementia

  2022cited by this paper
• Endoplasmic reticulum-mitochondria signaling in neurons and neurodegenerative diseases.

  2022cited by this paper
• Determining and interpreting protein lifetimes in mammalian tissues.

  2022cited by this paper
• Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.

  2022cited by this paper
• Protein network analysis to prioritize key genes in amyotrophic lateral sclerosis

  2021cited by this paper
• Proteostatic imbalance and protein spreading in amyotrophic lateral sclerosis

  2021cited by this paper
• Single-cell transcriptomics identifies master regulators of neurodegeneration in SOD1 ALS iPSC-derived motor neurons

  2021cited by this paper
• The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets

  2020cited by this paper
• The Neglected Genes of ALS: Cytoskeletal Dynamics Impact Synaptic Degeneration in ALS

  2020cited by this paper
• Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.

  2020cited by this paper
• Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function

  2020cited by this paper
• Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense-Mediated Decay as Modifiers of ALS/FTD C9orf72 Toxicity.

  2020cited by this paper
• Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals.

  2020cited by this paper
• PANTHER version 16: a revised family classification, tree-based classification tool, enhancer regions and extensive API

  2020cited by this paper
• Proteome Homeostasis Dysfunction: A Unifying Principle in ALS Pathogenesis.

  2020cited by this paper
• SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS.

  2020cited by this paper
• Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.

  2020cited by this paper
• A Stem Cell-Based Screening Platform Identifies Compounds that Desensitize Motor Neurons to Endoplasmic Reticulum Stress.

  2019cited by this paper
• Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense Mediated Decay as Modifiers of ALS C9orf72 Toxicity

  2019cited by this paper
• Identification and therapeutic rescue of autophagosome and glutamate receptor defects in C9ORF72 and sporadic ALS neurons.

  2019cited by this paper
• Multisystem Proteinopathy Mutations in VCP/p97 Increase NPLOC4·UFD1L Binding and Substrate Processing.

  2019cited by this paper
• ALS IMPLICATED PROTEIN TDP-43 SUSTAINS LEVELS OF STMN2 A MEDIATOR OF MOTOR NEURON GROWTH AND REPAIR

  2019cited by this paper
• Genetic Convergence Brings Clarity to the Enigmatic Red Line in ALS.

  2019cited by this paper
• VCP/p97 increases BMP signaling by accelerating ubiquitin ligase Smurf1 degradation

  2018cited by this paper
• Transcription Factor–Mediated Differentiation of Human iPSCs into Neurons

  2018cited by this paper
• Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis

  2018cited by this paper
• Single copy/knock-in models of ALS SOD1 in C. elegans suggest loss and gain of function have different contributions to cholinergic and glutamatergic neurodegeneration

  2018cited by this paper
• The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension

  2018cited by this paper
• Endoplasmic reticulum stress leads to accumulation of wild-type SOD1 aggregates associated with sporadic amyotrophic lateral sclerosis

  2018cited by this paper
• SOD1A4V aggregation alters ubiquitin homeostasis in a cell model of ALS

  2018cited by this paper
• The AAA+ ATPase p97, a cellular multitool

  2017cited by this paper
• Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L is enhanced by a mutation that causes multisystem proteinopathy

  2017cited by this paper
• A Mighty “Protein Extractor” of the Cell: Structure and Function of the p97/CDC48 ATPase

  2017cited by this paper
• VCP/p97-Mediated Unfolding as a Principle in Protein Homeostasis and Signaling.

  2017cited by this paper
• The Interplay of Cofactor Interactions and Post-translational Modifications in the Regulation of the AAA+ ATPase p97

  2017cited by this paper
• Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations

  2017cited by this paper
• Amyotrophic Lateral Sclerosis

  2017cited by this paper
• Silencing strategies for therapy of SOD1-mediated ALS.

  2017cited by this paper
• Mutations in valosin-containing protein (VCP) decrease ADP/ATP translocation across the mitochondrial membrane and impair energy metabolism in human neurons

  2017cited by this paper
• SOD1 in neurotoxicity and its controversial roles in SOD1 mutation-negative ALS.

  2016cited by this paper
• Modeling ALS with motor neurons derived from human induced pluripotent stem cells

  2016cited by this paper
• VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington's disease

  2016cited by this paper
• ALS disrupts spinal motor neuron maturation and aging pathways within gene co-expression networks

  2016cited by this paper
• ALS-linked misfolded SOD1 species have divergent impacts on mitochondria

  2016cited by this paper
• Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease.

  2016cited by this paper
• C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

  2016cited by this paper
• Effects of Cellular Pathway Disturbances on Misfolded Superoxide Dismutase-1 in Fibroblasts Derived from ALS Patients

  2016cited by this paper
• Valosin-containing protein (VCP)–Adaptor Interactions are Exceptionally Dynamic and Subject to Differential Modulation by a VCP Inhibitor *

  2016cited by this paper
• Inhibition of Cytohesins Protects against Genetic Models of Motor Neuron Disease

  2015cited by this paper
• Investigating the spreading and toxicity of prion-like proteins using the metazoan model organism C. elegans.

  2015cited by this paper
• The C9orf72 repeat expansion disrupts nucleocytoplasmic transport

  2015cited by this paper
• Extracting Accurate Precursor Information for Tandem Mass Spectra by RawConverter.

  2015cited by this paper
• ProLuCID: An improved SEQUEST-like algorithm with enhanced sensitivity and specificity.

  2015cited by this paper
• Loss of RAD-23 Protects Against Models of Motor Neuron Disease by Enhancing Mutant Protein Clearance

  2015cited by this paper
• Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons.

  2014cited by this paper
• Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia

  2014cited by this paper
• Experimental transmissibility of mutant SOD1 motor neuron disease

  2014cited by this paper
• Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1.

  2014cited by this paper
• Deregulated expression of cytoskeleton related genes in the spinal cord and sciatic nerve of presymptomatic SOD1G93A Amyotrophic Lateral Sclerosis mouse model

  2014cited by this paper
• The p97-UFD1L-NPL4 Protein Complex Mediates Cytokine-Induced IκBα Proteolysis

  2013cited by this paper
• Amyotrophic lateral sclerosis: Problems and prospects

  2013cited by this paper
• Complex of Fas-associated Factor 1 (FAF1) with Valosin-containing Protein (VCP)-Npl4-Ufd1 and Polyubiquitinated Proteins Promotes Endoplasmic Reticulum-associated Degradation (ERAD)*

  2013cited by this paper
• An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis

  2013cited by this paper
• VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations.

  2013cited by this paper
• The genetics and neuropathology of amyotrophic lateral sclerosis

  2012cited by this paper
• Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease

  2012cited by this paper
• Daf-2 Signaling Modifies Mutant SOD1 Toxicity in C. elegans

  2012cited by this paper
• Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system

  2012cited by this paper
• ALSoD: A user‐friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics

  2012cited by this paper
• Misfolded superoxide dismutase‐1 in CSF from amyotrophic lateral sclerosis patients

  2011cited by this paper
• Census for Proteome Quantification

  2010cited by this paper
• VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD

  2010cited by this paper
• [Amyotrophic lateral sclerosis].

  2010cited by this paper
• Exome sequencing reveals VCP mutations as a cause of familial ALS.

  2010cited by this paper
• Superoxide dismutase in amyotrophic lateral sclerosis patients homozygous for the D90A mutation.

  2009cited by this paper
• A role for motoneuron subtype–selective ER stress in disease manifestations of FALS mice

  2009cited by this paper
• An ALS-Linked Mutant SOD1 Produces a Locomotor Defect Associated with Aggregation and Synaptic Dysfunction When Expressed in Neurons of Caenorhabditis elegans

  2009cited by this paper
• Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease

  2009cited by this paper
• ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.

  2008cited by this paper
• Quantitative proteomic analysis of primary neurons reveals diverse changes in synaptic protein content in fmr1 knockout mice

  2008cited by this paper
• Impaired Protein Aggregate Handling and Clearance Underlie the Pathogenesis of p97/VCP-associated Disease*

  2008cited by this paper
• The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy

  2007cited by this paper
• Validation of Tandem Mass Spectrometry Database Search Results Using DTASelect

  2006cited by this paper
• Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria.

  2006cited by this paper
• Valosin-containing protein (p97) is a regulator of endoplasmic reticulum stress and of the degradation of N-end rule and ubiquitin-fusion degradation pathway substrates in mammalian cells.

  2006cited by this paper
• Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials

  2006cited by this paper
• Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation.

  2006cited by this paper
• WebGestalt: an integrated system for exploring gene sets in various biological contexts

  2005cited by this paper
• Analysis of the two p97/VCP/Cdc48p proteins of Caenorhabditis elegans and their suppression of polyglutamine-induced protein aggregation.

  2004cited by this paper
• Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein

  2004cited by this paper
• AAA ATPase p97/Valosin-containing Protein Interacts with gp78, a Ubiquitin Ligase for Endoplasmic Reticulum-associated Degradation*

  2004cited by this paper
• Evaluation of multidimensional chromatography coupled with tandem mass spectrometry (LC/LC-MS/MS) for large-scale protein analysis: the yeast proteome.

  2003cited by this paper
• DTASelect and Contrast: tools for assembling and comparing protein identifications from shotgun proteomics.

  2002cited by this paper
• Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS)

  2002cited by this paper
• The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol

  2001cited by this paper
• Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1.

  2000cited by this paper
• Oxidative Stress and Motor Neurone Disease

  1999cited by this paper
• Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.

  1996cited by this paper
• Altered Reactivity of Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis

  1996cited by this paper
• An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database

  1994cited by this paper

• Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.

  2026cites this paper
• Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics

  2025cites this paper
• Studying the mechanisms of neurodegeneration: C. elegans advantages and opportunities

  2025cites this paper
• Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers

  2025cites this paper
• The Iroquois (Iro/Irx) homeobox genes are conserved Hox targets involved in motor neuron development

  2025cites this paper
• Role of Fibroblast Growth Factors in Neurological Disorders: Insight into Therapeutic Approaches and Molecular Mechanisms

  2025cites this paper
• Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses

  2025cites this paper
• Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis

  2025cites this paper
• Phenotypical reflection of a patient with a possible pathological variation of the vcp gene and difficulties in neuromuscular differential diagnosis

  2025cites this paper
• Age-Related Neurodegenerative Diseases: A Stem Cell’s Perspective

  2025cites this paper
• 2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy.

  2025cites this paper
• Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derived C9orf72-associated ALS/FTD motor neurons

  2024cites this paper
• From use of omics to systems biology: Identifying therapeutic targets for amyotrophic lateral sclerosis.

  2024cites this paper
• The Iroquois (Iro/Irx) homeobox genes are conserved Hox targets involved in motor neuron development

  2024cites this paper
• Tracing ALS Degeneration: Insights from Spinal Cord and Cortex Transcriptomes

  2024cites this paper
• The ALS-associated co-chaperone DNAJC7 mediates neuroprotection against proteotoxic stress by modulating HSF1 activity

  2024cites this paper
• Simple models to understand complex disease: 10 years of progress from Caenorhabditis elegans models of amyotrophic lateral sclerosis and frontotemporal lobar degeneration

  2024cites this paper
• Vcp overexpression and leucine supplementation extend lifespan and ameliorate neuromuscular junction phenotypes of a SOD1G93A-ALS mouse model

  2024cites this paper