Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in α-Synuclein Aggregation Disorders
Accumulation of aggregated α-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson's disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how α-synuclein aggr...
Main Authors: | , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2018-05-01
|
Series: | EBioMedicine |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396418301622 |
id |
doaj-1a369182b6fc429891ec416beb23e350 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Scott Ugras Malcolm J. Daniels Hossein Fazelinia Neal S. Gould Anastasia K. Yocum Kelvin C. Luk Esteban Luna Hua Ding Chris McKennan Steven Seeholzer Dan Martinez Perry Evans Daniel Brown John E. Duda Harry Ischiropoulos |
spellingShingle |
Scott Ugras Malcolm J. Daniels Hossein Fazelinia Neal S. Gould Anastasia K. Yocum Kelvin C. Luk Esteban Luna Hua Ding Chris McKennan Steven Seeholzer Dan Martinez Perry Evans Daniel Brown John E. Duda Harry Ischiropoulos Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in α-Synuclein Aggregation Disorders EBioMedicine |
author_facet |
Scott Ugras Malcolm J. Daniels Hossein Fazelinia Neal S. Gould Anastasia K. Yocum Kelvin C. Luk Esteban Luna Hua Ding Chris McKennan Steven Seeholzer Dan Martinez Perry Evans Daniel Brown John E. Duda Harry Ischiropoulos |
author_sort |
Scott Ugras |
title |
Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in α-Synuclein Aggregation Disorders |
title_short |
Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in α-Synuclein Aggregation Disorders |
title_full |
Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in α-Synuclein Aggregation Disorders |
title_fullStr |
Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in α-Synuclein Aggregation Disorders |
title_full_unstemmed |
Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in α-Synuclein Aggregation Disorders |
title_sort |
induction of the immunoproteasome subunit lmp7 links proteostasis and immunity in α-synuclein aggregation disorders |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2018-05-01 |
description |
Accumulation of aggregated α-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson's disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how α-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of α-synuclein aggregation, 6% of 6215 proteins and 1.6% of 8183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling. The proteomic analysis confirmed changes in abundance of proteins that regulate dopamine synthesis and transport, synaptic activity and integrity, and unearthed changes in mRNA binding, processing and protein translation. Phosphorylation signaling changes centered on axonal and synaptic cytoskeletal organization and structural integrity. Proteostatic responses included a significant increase in the levels of Lmp7, a component of the immunoproteasome. Increased Lmp7 levels and activity were also quantified in postmortem human brains with PD and dementia with Lewy bodies. Functionally, the immunoproteasome degrades α-synuclein aggregates and generates potentially antigenic peptides. Expression and activity of the immunoproteasome may represent testable targets to induce adaptive responses that maintain proteome integrity and modulate immune responses in protein aggregation disorders. Keywords: Neurodegeneration, Parkinson's disease, Dopaminergic neurons, Immunoproteasome, Proteostasis |
url |
http://www.sciencedirect.com/science/article/pii/S2352396418301622 |
work_keys_str_mv |
AT scottugras inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT malcolmjdaniels inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT hosseinfazelinia inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT nealsgould inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT anastasiakyocum inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT kelvincluk inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT estebanluna inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT huading inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT chrismckennan inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT stevenseeholzer inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT danmartinez inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT perryevans inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT danielbrown inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT johneduda inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders AT harryischiropoulos inductionoftheimmunoproteasomesubunitlmp7linksproteostasisandimmunityinasynucleinaggregationdisorders |
_version_ |
1725922198134194176 |
spelling |
doaj-1a369182b6fc429891ec416beb23e3502020-11-24T21:41:24ZengElsevierEBioMedicine2352-39642018-05-0131307319Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in α-Synuclein Aggregation DisordersScott Ugras0Malcolm J. Daniels1Hossein Fazelinia2Neal S. Gould3Anastasia K. Yocum4Kelvin C. Luk5Esteban Luna6Hua Ding7Chris McKennan8Steven Seeholzer9Dan Martinez10Perry Evans11Daniel Brown12John E. Duda13Harry Ischiropoulos14Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAPharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAChildren's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USAChildren's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USAA2IDEA, LLC, Ann Arbor, MI 48105, USACenter for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USACenter for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAChildren's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USAChildren's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA; Department of Statistics, University of Chicago, 60637, USAChildren's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USAChildren's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USADepartment of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USAParkinson's Disease Research, Education and Clinical Center, Michael J. Crescenz VA Medical Center, USA; Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, USAParkinson's Disease Research, Education and Clinical Center, Michael J. Crescenz VA Medical Center, USA; Neurology, Perelman School of Medicine, University of Pennsylvania, USABiochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA; Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pediatrics, Children's Hospital of Philadelphia Research Institute and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author at: Department of Pediatrics, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.Accumulation of aggregated α-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson's disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how α-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of α-synuclein aggregation, 6% of 6215 proteins and 1.6% of 8183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling. The proteomic analysis confirmed changes in abundance of proteins that regulate dopamine synthesis and transport, synaptic activity and integrity, and unearthed changes in mRNA binding, processing and protein translation. Phosphorylation signaling changes centered on axonal and synaptic cytoskeletal organization and structural integrity. Proteostatic responses included a significant increase in the levels of Lmp7, a component of the immunoproteasome. Increased Lmp7 levels and activity were also quantified in postmortem human brains with PD and dementia with Lewy bodies. Functionally, the immunoproteasome degrades α-synuclein aggregates and generates potentially antigenic peptides. Expression and activity of the immunoproteasome may represent testable targets to induce adaptive responses that maintain proteome integrity and modulate immune responses in protein aggregation disorders. Keywords: Neurodegeneration, Parkinson's disease, Dopaminergic neurons, Immunoproteasome, Proteostasishttp://www.sciencedirect.com/science/article/pii/S2352396418301622 |